Skip to main content
NCBI home page
Biophysical Journal logoLink to Biophysical Journal
. 1998 Aug;75(2):612–634. doi: 10.1016/S0006-3495(98)77552-6

Opioid receptor three-dimensional structures from distance geometry calculations with hydrogen bonding constraints.

I D Pogozheva 1, A L Lomize 1, H I Mosberg 1
PMCID: PMC1299737  PMID: 9675164

Abstract

Three-dimensional structures of the transmembrane, seven alpha-helical domains and extracellular loops of delta, mu, and kappa opioid receptors, were calculated using the distance geometry algorithm, with hydrogen bonding constraints based on the previously developed general model of the transmembrane alpha-bundle for rhodopsin-like G-protein coupled receptors (Biophys. J. 1997. 70:1963). Each calculated opioid receptor structure has an extensive network of interhelical hydrogen bonds and a ligand-binding crevice that is partially covered by a beta-hairpin formed by the second extracellular loop. The binding cavities consist of an inner "conserved region" composed of 18 residues that are identical in delta, mu, and kappa opioid receptors, and a peripheral "variable region," composed of 19 residues that are different in delta, mu, and kappa subtypes and are responsible for the subtype specificity of various ligands. Sixteen delta-, mu-, or kappa-selective, conformationally constrained peptide and nonpeptide opioid agonists and antagonists and affinity labels were fit into the binding pockets of the opioid receptors. All ligands considered have a similar spatial arrangement in the receptors, with the tyramine moiety of alkaloids or Tyr1 of opioid peptides interacting with conserved residues in the bottom of the pocket and the tyramine N+ and OH groups forming ionic interactions or H-bonds with a conserved aspartate from helix III and a conserved histidine from helix VI, respectively. The central, conformationally constrained fragments of the opioids (the disulfide-bridged cycles of the peptides and various ring structures in the nonpeptide ligands) are oriented approximately perpendicular to the tyramine and directed toward the extracellular surface. The results obtained are qualitatively consistent with ligand affinities, cross-linking studies, and mutagenesis data.

Full Text

The Full Text of this article is available as a PDF (559.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alkorta I., Loew G. H. A 3D model of the delta opioid receptor and ligand-receptor complexes. Protein Eng. 1996 Jul;9(7):573–583. doi: 10.1093/protein/9.7.573. [DOI] [PubMed] [Google Scholar]
  2. Baldwin E. P., Hajiseyedjavadi O., Baase W. A., Matthews B. W. The role of backbone flexibility in the accommodation of variants that repack the core of T4 lysozyme. Science. 1993 Dec 10;262(5140):1715–1718. doi: 10.1126/science.8259514. [DOI] [PubMed] [Google Scholar]
  3. Baldwin E., Xu J., Hajiseyedjavadi O., Baase W. A., Matthews B. W. Thermodynamic and structural compensation in "size-switch" core repacking variants of bacteriophage T4 lysozyme. J Mol Biol. 1996 Jun 14;259(3):542–559. doi: 10.1006/jmbi.1996.0338. [DOI] [PubMed] [Google Scholar]
  4. Baldwin J. M., Schertler G. F., Unger V. M. An alpha-carbon template for the transmembrane helices in the rhodopsin family of G-protein-coupled receptors. J Mol Biol. 1997 Sep 12;272(1):144–164. doi: 10.1006/jmbi.1997.1240. [DOI] [PubMed] [Google Scholar]
  5. Baldwin J. M. The probable arrangement of the helices in G protein-coupled receptors. EMBO J. 1993 Apr;12(4):1693–1703. doi: 10.1002/j.1460-2075.1993.tb05814.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Barlow D. J., Thornton J. M. Helix geometry in proteins. J Mol Biol. 1988 Jun 5;201(3):601–619. doi: 10.1016/0022-2836(88)90641-9. [DOI] [PubMed] [Google Scholar]
  7. Befort K., Tabbara L., Bausch S., Chavkin C., Evans C., Kieffer B. The conserved aspartate residue in the third putative transmembrane domain of the delta-opioid receptor is not the anionic counterpart for cationic opiate binding but is a constituent of the receptor binding site. Mol Pharmacol. 1996 Feb;49(2):216–223. [PubMed] [Google Scholar]
  8. Befort K., Tabbara L., Kling D., Maigret B., Kieffer B. L. Role of aromatic transmembrane residues of the delta-opioid receptor in ligand recognition. J Biol Chem. 1996 Apr 26;271(17):10161–10168. doi: 10.1074/jbc.271.17.10161. [DOI] [PubMed] [Google Scholar]
  9. Bernstein F. C., Koetzle T. F., Williams G. J., Meyer E. F., Jr, Brice M. D., Rodgers J. R., Kennard O., Shimanouchi T., Tasumi M. The Protein Data Bank: a computer-based archival file for macromolecular structures. J Mol Biol. 1977 May 25;112(3):535–542. doi: 10.1016/s0022-2836(77)80200-3. [DOI] [PubMed] [Google Scholar]
  10. Bidlack J. M., Frey D. K., Seyed-Mozaffari A., Archer S. 14 beta-(Bromoacetamido)morphine irreversibly labels mu opioid receptors in rat brain membranes. Biochemistry. 1989 May 16;28(10):4333–4339. doi: 10.1021/bi00436a031. [DOI] [PubMed] [Google Scholar]
  11. Calderon S. N., Rice K. C., Rothman R. B., Porreca F., Flippen-Anderson J. L., Kayakiri H., Xu H., Becketts K., Smith L. E., Bilsky E. J. Probes for narcotic receptor mediated phenomena. 23. Synthesis, opioid receptor binding, and bioassay of the highly selective delta agonist (+)-4-[(alpha R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N,N-diethylbenzamide (SNC 80) and related novel nonpeptide delta opioid receptor ligands. J Med Chem. 1997 Feb 28;40(5):695–704. doi: 10.1021/jm960319n. [DOI] [PubMed] [Google Scholar]
  12. Cappelli A., Anzini M., Vomero S., Menziani M. C., De Benedetti P. G., Sbacchi M., Clarke G. D., Mennuni L. Synthesis, biological evaluation, and quantitative receptor docking simulations of 2-[(acylamino)ethyl]-1,4-benzodiazepines as novel tifluadom-like ligands with high affinity and selectivity for kappa-opioid receptors. J Med Chem. 1996 Feb 16;39(4):860–872. doi: 10.1021/jm950423p. [DOI] [PubMed] [Google Scholar]
  13. Chakrabarti S., Yang W., Law P. Y., Loh H. H. The mu-opioid receptor down-regulates differently from the delta-opioid receptor: requirement of a high affinity receptor/G protein complex formation. Mol Pharmacol. 1997 Jul;52(1):105–113. [PubMed] [Google Scholar]
  14. Chang A. C., Takemori A. E., Ojala W. H., Gleason W. B., Portoghese P. S. kappa Opioid receptor selective affinity labels: electrophilic benzeneacetamides as kappa-selective opioid antagonists. J Med Chem. 1994 Dec 23;37(26):4490–4498. doi: 10.1021/jm00052a008. [DOI] [PubMed] [Google Scholar]
  15. Chen C., Xue J. C., Zhu J., Chen Y. W., Kunapuli S., Kim de Riel J., Yu L., Liu-Chen L. Y. Characterization of irreversible binding of beta-funaltrexamine to the cloned rat mu opioid receptor. J Biol Chem. 1995 Jul 28;270(30):17866–17870. doi: 10.1074/jbc.270.30.17866. [DOI] [PubMed] [Google Scholar]
  16. Chen C., Yin J., Riel J. K., DesJarlais R. L., Raveglia L. F., Zhu J., Liu-Chen L. Y. Determination of the amino acid residue involved in [3H]beta-funaltrexamine covalent binding in the cloned rat mu-opioid receptor. J Biol Chem. 1996 Aug 30;271(35):21422–21429. doi: 10.1074/jbc.271.35.21422. [DOI] [PubMed] [Google Scholar]
  17. Chothia C., Lesk A. M. Helix movements and the reconstruction of the haem pocket during the evolution of the cytochrome c family. J Mol Biol. 1985 Mar 5;182(1):151–158. doi: 10.1016/0022-2836(85)90033-6. [DOI] [PubMed] [Google Scholar]
  18. Claude P. A., Wotta D. R., Zhang X. H., Prather P. L., McGinn T. M., Erickson L. J., Loh H. H., Law P. Y. Mutation of a conserved serine in TM4 of opioid receptors confers full agonistic properties to classical antagonists. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5715–5719. doi: 10.1073/pnas.93.12.5715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Daopin S., Alber T., Baase W. A., Wozniak J. A., Matthews B. W. Structural and thermodynamic analysis of the packing of two alpha-helices in bacteriophage T4 lysozyme. J Mol Biol. 1991 Sep 20;221(2):647–667. doi: 10.1016/0022-2836(91)80079-a. [DOI] [PubMed] [Google Scholar]
  20. Davies A., Schertler G. F., Gowen B. E., Saibil H. R. Projection structure of an invertebrate rhodopsin. J Struct Biol. 1996 Jul-Aug;117(1):36–44. doi: 10.1006/jsbi.1996.0067. [DOI] [PubMed] [Google Scholar]
  21. Deisenhofer J., Michel H. Structures of bacterial photosynthetic reaction centers. Annu Rev Cell Biol. 1991;7:1–23. doi: 10.1146/annurev.cb.07.110191.000245. [DOI] [PubMed] [Google Scholar]
  22. Deschamps J. R., George C., Flippen-Anderson J. L. Structural studies of opioid peptides: a review of recent progress in x-ray diffraction studies. Biopolymers. 1996;40(1):121–139. doi: 10.1002/bip.360400102. [DOI] [PubMed] [Google Scholar]
  23. Dhawan B. N., Cesselin F., Raghubir R., Reisine T., Bradley P. B., Portoghese P. S., Hamon M. International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol Rev. 1996 Dec;48(4):567–592. [PubMed] [Google Scholar]
  24. Doi M., Ishida T., Inoue M. Conformational characteristics of opioid kappa-receptor agonist: crystal structure of (5S,7S,8S)-(-)-N-methyl-N-[7-(1-pyrrolidinyl)-1- oxaspiro[4.5]dec-8-yl]benzeneacetamide (U69,593), and conformational comparison with some kappa-agonists. Chem Pharm Bull (Tokyo) 1990 Jul;38(7):1815–1818. doi: 10.1248/cpb.38.1815. [DOI] [PubMed] [Google Scholar]
  25. Donnelly D., Findlay J. B., Blundell T. L. The evolution and structure of aminergic G protein-coupled receptors. Receptors Channels. 1994;2(1):61–78. [PubMed] [Google Scholar]
  26. Elling C. E., Nielsen S. M., Schwartz T. W. Conversion of antagonist-binding site to metal-ion site in the tachykinin NK-1 receptor. Nature. 1995 Mar 2;374(6517):74–77. doi: 10.1038/374074a0. [DOI] [PubMed] [Google Scholar]
  27. Eriksson A. E., Baase W. A., Zhang X. J., Heinz D. W., Blaber M., Baldwin E. P., Matthews B. W. Response of a protein structure to cavity-creating mutations and its relation to the hydrophobic effect. Science. 1992 Jan 10;255(5041):178–183. doi: 10.1126/science.1553543. [DOI] [PubMed] [Google Scholar]
  28. Fahmy K., Siebert F., Sakmar T. P. Photoactivated state of rhodopsin and how it can form. Biophys Chem. 1995 Sep-Oct;56(1-2):171–181. doi: 10.1016/0301-4622(95)00030-2. [DOI] [PubMed] [Google Scholar]
  29. Farrens D. L., Altenbach C., Yang K., Hubbell W. L., Khorana H. G. Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin. Science. 1996 Nov 1;274(5288):768–770. doi: 10.1126/science.274.5288.768. [DOI] [PubMed] [Google Scholar]
  30. Fernandez L. M., Puett D. Lys583 in the third extracellular loop of the lutropin/choriogonadotropin receptor is critical for signaling. J Biol Chem. 1996 Jan 12;271(2):925–930. doi: 10.1074/jbc.271.2.925. [DOI] [PubMed] [Google Scholar]
  31. Fraser C. M., Wang C. D., Robinson D. A., Gocayne J. D., Venter J. C. Site-directed mutagenesis of m1 muscarinic acetylcholine receptors: conserved aspartic acids play important roles in receptor function. Mol Pharmacol. 1989 Dec;36(6):840–847. [PubMed] [Google Scholar]
  32. Froimowitz M. Conformational search in enkephalin analogues containing a disulfide bond. Biopolymers. 1990;30(11-12):1011–1025. doi: 10.1002/bip.360301103. [DOI] [PubMed] [Google Scholar]
  33. Fu D., Ballesteros J. A., Weinstein H., Chen J., Javitch J. A. Residues in the seventh membrane-spanning segment of the dopamine D2 receptor accessible in the binding-site crevice. Biochemistry. 1996 Sep 3;35(35):11278–11285. doi: 10.1021/bi960928x. [DOI] [PubMed] [Google Scholar]
  34. Fukuda K., Terasako K., Kato S., Mori K. Identification of the amino acid residues involved in selective agonist binding in the first extracellular loop of the delta- and mu-opioid receptors. FEBS Lett. 1995 Oct 9;373(2):177–181. doi: 10.1016/0014-5793(95)01034-c. [DOI] [PubMed] [Google Scholar]
  35. Griffin J. F., Larson D. L., Portoghese P. S. Crystal structures of alpha- and beta-funaltrexamine: conformational requirement of the fumaramate moiety in the irreversible blockage of mu opioid receptors. J Med Chem. 1986 May;29(5):778–783. doi: 10.1021/jm00155a031. [DOI] [PubMed] [Google Scholar]
  36. Grigorieff N., Ceska T. A., Downing K. H., Baldwin J. M., Henderson R. Electron-crystallographic refinement of the structure of bacteriorhodopsin. J Mol Biol. 1996 Jun 14;259(3):393–421. doi: 10.1006/jmbi.1996.0328. [DOI] [PubMed] [Google Scholar]
  37. Güntert P., Braun W., Wüthrich K. Efficient computation of three-dimensional protein structures in solution from nuclear magnetic resonance data using the program DIANA and the supporting programs CALIBA, HABAS and GLOMSA. J Mol Biol. 1991 Feb 5;217(3):517–530. doi: 10.1016/0022-2836(91)90754-t. [DOI] [PubMed] [Google Scholar]
  38. Güntert P., Wüthrich K. Improved efficiency of protein structure calculations from NMR data using the program DIANA with redundant dihedral angle constraints. J Biomol NMR. 1991 Nov;1(4):447–456. doi: 10.1007/BF02192866. [DOI] [PubMed] [Google Scholar]
  39. Haaseth R. C., Horan P. J., Bilsky E. J., Davis P., Zalewska T., Slaninova J., Yamamura H. I., Weber S. J., Davis T. P., Porreca F. [L-Ala3]DPDPE: a new enkephalin analog with a unique opioid receptor activity profile. Further evidence of delta-opioid receptor multiplicity. J Med Chem. 1994 May 27;37(11):1572–1577. doi: 10.1021/jm00037a007. [DOI] [PubMed] [Google Scholar]
  40. Han M., Lin S. W., Minkova M., Smith S. O., Sakmar T. P. Functional interaction of transmembrane helices 3 and 6 in rhodopsin. Replacement of phenylalanine 261 by alanine causes reversion of phenotype of a glycine 121 replacement mutant. J Biol Chem. 1996 Dec 13;271(50):32337–32342. doi: 10.1074/jbc.271.50.32337. [DOI] [PubMed] [Google Scholar]
  41. Han M., Lin S. W., Smith S. O., Sakmar T. P. The effects of amino acid replacements of glycine 121 on transmembrane helix 3 of rhodopsin. J Biol Chem. 1996 Dec 13;271(50):32330–32336. doi: 10.1074/jbc.271.50.32330. [DOI] [PubMed] [Google Scholar]
  42. Henderson R., Baldwin J. M., Ceska T. A., Zemlin F., Beckmann E., Downing K. H. Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy. J Mol Biol. 1990 Jun 20;213(4):899–929. doi: 10.1016/S0022-2836(05)80271-2. [DOI] [PubMed] [Google Scholar]
  43. Herzyk P., Hubbard R. E. Automated method for modeling seven-helix transmembrane receptors from experimental data. Biophys J. 1995 Dec;69(6):2419–2442. doi: 10.1016/S0006-3495(95)80112-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Heyl D. L., Mosberg H. I. Modification of the Phe3 aromatic moiety in delta receptor-selective dermorphin/deltorphin-related tetrapeptides. Effects on opioid receptor binding. Int J Pept Protein Res. 1992 May;39(5):450–457. doi: 10.1111/j.1399-3011.1992.tb01449.x. [DOI] [PubMed] [Google Scholar]
  45. Heyl D. L., Mosberg H. I. Substitution on the Phe3 aromatic ring in cyclic delta opioid receptor-selective dermorphin/deltorphin tetrapeptide analogues: electronic and lipophilic requirements for receptor affinity. J Med Chem. 1992 May 1;35(9):1535–1541. doi: 10.1021/jm00087a006. [DOI] [PubMed] [Google Scholar]
  46. Hjorth S. A., Thirstrup K., Grandy D. K., Schwartz T. W. Analysis of selective binding epitopes for the kappa-opioid receptor antagonist nor-binaltorphimine. Mol Pharmacol. 1995 Jun;47(6):1089–1094. [PubMed] [Google Scholar]
  47. Ho B. Y., Karschin A., Branchek T., Davidson N., Lester H. A. The role of conserved aspartate and serine residues in ligand binding and in function of the 5-HT1A receptor: a site-directed mutation study. FEBS Lett. 1992 Nov 9;312(2-3):259–262. doi: 10.1016/0014-5793(92)80948-g. [DOI] [PubMed] [Google Scholar]
  48. Housset D., Kim K. S., Fuchs J., Woodward C., Wlodawer A. Crystal structure of a Y35G mutant of bovine pancreatic trypsin inhibitor. J Mol Biol. 1991 Aug 5;220(3):757–770. doi: 10.1016/0022-2836(91)90115-m. [DOI] [PubMed] [Google Scholar]
  49. Hwa J., Gaivin R., Porter J. E., Perez D. M. Synergism of constitutive activity in alpha 1-adrenergic receptor activation. Biochemistry. 1997 Jan 21;36(3):633–639. doi: 10.1021/bi962141c. [DOI] [PubMed] [Google Scholar]
  50. Javitch J. A., Fu D., Chen J., Karlin A. Mapping the binding-site crevice of the dopamine D2 receptor by the substituted-cysteine accessibility method. Neuron. 1995 Apr;14(4):825–831. doi: 10.1016/0896-6273(95)90226-0. [DOI] [PubMed] [Google Scholar]
  51. Javitch J. A., Li X., Kaback J., Karlin A. A cysteine residue in the third membrane-spanning segment of the human D2 dopamine receptor is exposed in the binding-site crevice. Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10355–10359. doi: 10.1073/pnas.91.22.10355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Knapp R. J., Malatynska E., Collins N., Fang L., Wang J. Y., Hruby V. J., Roeske W. R., Yamamura H. I. Molecular biology and pharmacology of cloned opioid receptors. FASEB J. 1995 Apr;9(7):516–525. doi: 10.1096/fasebj.9.7.7737460. [DOI] [PubMed] [Google Scholar]
  53. Kong H., Raynor K., Yano H., Takeda J., Bell G. I., Reisine T. Agonists and antagonists bind to different domains of the cloned kappa opioid receptor. Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8042–8046. doi: 10.1073/pnas.91.17.8042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Kong H., Raynor K., Yasuda K., Moe S. T., Portoghese P. S., Bell G. I., Reisine T. A single residue, aspartic acid 95, in the delta opioid receptor specifies selective high affinity agonist binding. J Biol Chem. 1993 Nov 5;268(31):23055–23058. [PubMed] [Google Scholar]
  55. Lahti R. A., Mickelson M. M., McCall J. M., Von Voigtlander P. F. [3H]U-69593 a highly selective ligand for the opioid kappa receptor. Eur J Pharmacol. 1985 Feb 26;109(2):281–284. doi: 10.1016/0014-2999(85)90431-5. [DOI] [PubMed] [Google Scholar]
  56. Lesk A. M., Chothia C. How different amino acid sequences determine similar protein structures: the structure and evolutionary dynamics of the globins. J Mol Biol. 1980 Jan 25;136(3):225–270. doi: 10.1016/0022-2836(80)90373-3. [DOI] [PubMed] [Google Scholar]
  57. Lomize A. L., Pogozheva I. D., Mosberg H. I. Development of a model for the delta-opioid receptor pharmacophore: 3. Comparison of the cyclic tetrapeptide, Tyr-c[D-Cys-Phe-D-Pen]OH with other conformationally constrained delta-receptor selective ligands. Biopolymers. 1996 Feb;38(2):221–234. doi: 10.1002/(SICI)1097-0282(199602)38:2%3C221::AID-BIP8%3E3.0.CO;2-X. [DOI] [PubMed] [Google Scholar]
  58. Louie G. V., Brayer G. D. A polypeptide chain-refolding event occurs in the Gly82 variant of yeast iso-1-cytochrome c. J Mol Biol. 1989 Nov 20;210(2):313–322. doi: 10.1016/0022-2836(89)90333-1. [DOI] [PubMed] [Google Scholar]
  59. Mansour A., Meng F., Meador-Woodruff J. H., Taylor L. P., Civelli O., Akil H. Site-directed mutagenesis of the human dopamine D2 receptor. Eur J Pharmacol. 1992 Oct 1;227(2):205–214. doi: 10.1016/0922-4106(92)90129-j. [DOI] [PubMed] [Google Scholar]
  60. Mansour A., Taylor L. P., Fine J. L., Thompson R. C., Hoversten M. T., Mosberg H. I., Watson S. J., Akil H. Key residues defining the mu-opioid receptor binding pocket: a site-directed mutagenesis study. J Neurochem. 1997 Jan;68(1):344–353. doi: 10.1046/j.1471-4159.1997.68010344.x. [DOI] [PubMed] [Google Scholar]
  61. McDonald I. K., Thornton J. M. Satisfying hydrogen bonding potential in proteins. J Mol Biol. 1994 May 20;238(5):777–793. doi: 10.1006/jmbi.1994.1334. [DOI] [PubMed] [Google Scholar]
  62. Meng F., Hoversten M. T., Thompson R. C., Taylor L., Watson S. J., Akil H. A chimeric study of the molecular basis of affinity and selectivity of the kappa and the delta opioid receptors. Potential role of extracellular domains. J Biol Chem. 1995 May 26;270(21):12730–12736. doi: 10.1074/jbc.270.21.12730. [DOI] [PubMed] [Google Scholar]
  63. Meng F., Ueda Y., Hoversten M. T., Thompson R. C., Taylor L., Watson S. J., Akil H. Mapping the receptor domains critical for the binding selectivity of delta-opioid receptor ligands. Eur J Pharmacol. 1996 Sep 12;311(2-3):285–292. doi: 10.1016/0014-2999(96)00431-1. [DOI] [PubMed] [Google Scholar]
  64. Metzger T. G., Ferguson D. M. On the role of extracellular loops of opioid receptors in conferring ligand selectivity. FEBS Lett. 1995 Nov 13;375(1-2):1–4. doi: 10.1016/0014-5793(95)01185-h. [DOI] [PubMed] [Google Scholar]
  65. Metzger T. G., Paterlini M. G., Portoghese P. S., Ferguson D. M. Application of the message-address concept to the docking of naltrexone and selective naltrexone-derived opioid antagonists into opioid receptor models. Neurochem Res. 1996 Nov;21(11):1287–1294. doi: 10.1007/BF02532369. [DOI] [PubMed] [Google Scholar]
  66. Minami M., Nakagawa T., Seki T., Onogi T., Aoki Y., Katao Y., Katsumata S., Satoh M. A single residue, Lys108, of the delta-opioid receptor prevents the mu-opioid-selective ligand [D-Ala2,N-MePhe4,Gly-ol5]enkephalin from binding to the delta-opioid receptor. Mol Pharmacol. 1996 Nov;50(5):1413–1422. [PubMed] [Google Scholar]
  67. Mosberg H. I., Dua R. K., Pogozheva I. D., Lomize A. L. Development of a model for the delta-opioid receptor pharmacophore. 4. Residue 3 dehydrophenylalanine analogues of Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) confirm required gauche orientation of aromatic side chain. Biopolymers. 1996 Sep;39(3):287–296. doi: 10.1002/(sici)1097-0282(199609)39:3<287::aid-bip2>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  68. Mosberg H. I., Hurst R., Hruby V. J., Gee K., Yamamura H. I., Galligan J. J., Burks T. F. Bis-penicillamine enkephalins possess highly improved specificity toward delta opioid receptors. Proc Natl Acad Sci U S A. 1983 Oct;80(19):5871–5874. doi: 10.1073/pnas.80.19.5871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Mosberg H. I., Lomize A. L., Wang C., Kroona H., Heyl D. L., Sobczyk-Kojiro K., Ma W., Mousigian C., Porreca F. Development of a model for the delta opioid receptor pharmacophore. 1. Conformationally restricted Tyr1 replacements in the cyclic delta receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13). J Med Chem. 1994 Dec 9;37(25):4371–4383. doi: 10.1021/jm00051a015. [DOI] [PubMed] [Google Scholar]
  70. Mosberg H. I., Omnaas J. R., Lomize A., Heyl D. L., Nordan I., Mousigian C., Davis P., Porreca F. Development of a model for the delta opioid receptor pharmacophore. 2. Conformationally restricted Phe3 replacements in the cyclic delta receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13). J Med Chem. 1994 Dec 9;37(25):4384–4391. doi: 10.1021/jm00051a016. [DOI] [PubMed] [Google Scholar]
  71. Mosberg H. I., Omnaas J. R., Medzihradsky F., Smith C. B. Cyclic, disulfide- and dithioether-containing opioid tetrapeptides: development of a ligand with high delta opioid receptor selectivity and affinity. Life Sci. 1988;43(12):1013–1020. doi: 10.1016/0024-3205(88)90547-4. [DOI] [PubMed] [Google Scholar]
  72. Onogi T., Minami M., Katao Y., Nakagawa T., Aoki Y., Toya T., Katsumata S., Satoh M. DAMGO, a mu-opioid receptor selective agonist, distinguishes between mu- and delta-opioid receptors around their first extracellular loops. FEBS Lett. 1995 Jan 2;357(1):93–97. doi: 10.1016/0014-5793(94)01341-w. [DOI] [PubMed] [Google Scholar]
  73. Pepin M. C., Yue S. Y., Roberts E., Wahlestedt C., Walker P. Novel "restoration of function" mutagenesis strategy to identify amino acids of the delta-opioid receptor involved in ligand binding. J Biol Chem. 1997 Apr 4;272(14):9260–9267. doi: 10.1074/jbc.272.14.9260. [DOI] [PubMed] [Google Scholar]
  74. Pogozheva I. D., Lomize A. L., Mosberg H. I. The transmembrane 7-alpha-bundle of rhodopsin: distance geometry calculations with hydrogen bonding constraints. Biophys J. 1997 May;72(5):1963–1985. doi: 10.1016/S0006-3495(97)78842-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Porter J. E., Hwa J., Perez D. M. Activation of the alpha1b-adrenergic receptor is initiated by disruption of an interhelical salt bridge constraint. J Biol Chem. 1996 Nov 8;271(45):28318–28323. doi: 10.1074/jbc.271.45.28318. [DOI] [PubMed] [Google Scholar]
  76. Portoghese A. S., Lipkowski A. W., Takemori A. E. Bimorphinans as highly selective, potent kappa opioid receptor antagonists. J Med Chem. 1987 Feb;30(2):238–239. doi: 10.1021/jm00385a002. [DOI] [PubMed] [Google Scholar]
  77. Portoghese P. S., Lin C. E., Farouz-Grant F., Takemori A. E. Structure-activity relationship of N17'-substituted norbinaltorphimine congeners. Role of the N17' basic group in the interaction with a putative address subsite on the kappa opioid receptor. J Med Chem. 1994 May 13;37(10):1495–1500. doi: 10.1021/jm00036a015. [DOI] [PubMed] [Google Scholar]
  78. Portoghese P. S., Sultana M., Takemori A. E. Design of peptidomimetic delta opioid receptor antagonists using the message-address concept. J Med Chem. 1990 Jun;33(6):1714–1720. doi: 10.1021/jm00168a028. [DOI] [PubMed] [Google Scholar]
  79. Reisine T. Opiate receptors. Neuropharmacology. 1995 May;34(5):463–472. doi: 10.1016/0028-3908(95)00025-2. [DOI] [PubMed] [Google Scholar]
  80. Robinson P. R., Cohen G. B., Zhukovsky E. A., Oprian D. D. Constitutively active mutants of rhodopsin. Neuron. 1992 Oct;9(4):719–725. doi: 10.1016/0896-6273(92)90034-b. [DOI] [PubMed] [Google Scholar]
  81. Römer D., Büscher H., Hill R. C., Maurer R., Petcher T. J., Welle H. B., Bakel H. C., Akkerman A. M. Bremazocine: a potent, long-acting opiate kappa-agonist. Life Sci. 1980 Sep 15;27(11):971–978. doi: 10.1016/0024-3205(80)90107-1. [DOI] [PubMed] [Google Scholar]
  82. Sauer U. H., San D. P., Matthews B. W. Tolerance of T4 lysozyme to proline substitutions within the long interdomain alpha-helix illustrates the adaptability of proteins to potentially destabilizing lesions. J Biol Chem. 1992 Feb 5;267(4):2393–2399. [PubMed] [Google Scholar]
  83. Savarese T. M., Fraser C. M. In vitro mutagenesis and the search for structure-function relationships among G protein-coupled receptors. Biochem J. 1992 Apr 1;283(Pt 1):1–19. doi: 10.1042/bj2830001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Schertler G. F., Villa C., Henderson R. Projection structure of rhodopsin. Nature. 1993 Apr 22;362(6422):770–772. doi: 10.1038/362770a0. [DOI] [PubMed] [Google Scholar]
  85. Sealfon S. C., Chi L., Ebersole B. J., Rodic V., Zhang D., Ballesteros J. A., Weinstein H. Related contribution of specific helix 2 and 7 residues to conformational activation of the serotonin 5-HT2A receptor. J Biol Chem. 1995 Jul 14;270(28):16683–16688. doi: 10.1074/jbc.270.28.16683. [DOI] [PubMed] [Google Scholar]
  86. Shahrestanifar M., Wang W. W., Howells R. D. Studies on inhibition of mu and delta opioid receptor binding by dithiothreitol and N-ethylmaleimide. His223 is critical for mu opioid receptor binding and inactivation by N-ethylmaleimide. J Biol Chem. 1996 Mar 8;271(10):5505–5512. doi: 10.1074/jbc.271.10.5505. [DOI] [PubMed] [Google Scholar]
  87. Sheikh S. P., Zvyaga T. A., Lichtarge O., Sakmar T. P., Bourne H. R. Rhodopsin activation blocked by metal-ion-binding sites linking transmembrane helices C and F. Nature. 1996 Sep 26;383(6598):347–350. doi: 10.1038/383347a0. [DOI] [PubMed] [Google Scholar]
  88. Shieh T., Han M., Sakmar T. P., Smith S. O. The steric trigger in rhodopsin activation. J Mol Biol. 1997 Jun 13;269(3):373–384. doi: 10.1006/jmbi.1997.1035. [DOI] [PubMed] [Google Scholar]
  89. Sibanda B. L., Thornton J. M. Conformation of beta hairpins in protein structures: classification and diversity in homologous structures. Methods Enzymol. 1991;202:59–82. doi: 10.1016/0076-6879(91)02007-v. [DOI] [PubMed] [Google Scholar]
  90. Strader C. D., Candelore M. R., Hill W. S., Sigal I. S., Dixon R. A. Identification of two serine residues involved in agonist activation of the beta-adrenergic receptor. J Biol Chem. 1989 Aug 15;264(23):13572–13578. [PubMed] [Google Scholar]
  91. Strader C. D., Sigal I. S., Candelore M. R., Rands E., Hill W. S., Dixon R. A. Conserved aspartic acid residues 79 and 113 of the beta-adrenergic receptor have different roles in receptor function. J Biol Chem. 1988 Jul 25;263(21):10267–10271. [PubMed] [Google Scholar]
  92. Strader C. D., Sigal I. S., Register R. B., Candelore M. R., Rands E., Dixon R. A. Identification of residues required for ligand binding to the beta-adrenergic receptor. Proc Natl Acad Sci U S A. 1987 Jul;84(13):4384–4388. doi: 10.1073/pnas.84.13.4384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Surratt C. K., Johnson P. S., Moriwaki A., Seidleck B. K., Blaschak C. J., Wang J. B., Uhl G. R. -mu opiate receptor. Charged transmembrane domain amino acids are critical for agonist recognition and intrinsic activity. J Biol Chem. 1994 Aug 12;269(32):20548–20553. [PubMed] [Google Scholar]
  94. Szmuszkovicz J., Von Voigtlander P. F. Benzeneacetamide amines: structurally novel non-m mu opioids. J Med Chem. 1982 Oct;25(10):1125–1126. doi: 10.1021/jm00352a005. [DOI] [PubMed] [Google Scholar]
  95. Takemori A. E., Portoghese P. S. Affinity labels for opioid receptors. Annu Rev Pharmacol Toxicol. 1985;25:193–223. doi: 10.1146/annurev.pa.25.040185.001205. [DOI] [PubMed] [Google Scholar]
  96. Thirstrup K., Elling C. E., Hjorth S. A., Schwartz T. W. Construction of a high affinity zinc switch in the kappa-opioid receptor. J Biol Chem. 1996 Apr 5;271(14):7875–7878. doi: 10.1074/jbc.271.14.7875. [DOI] [PubMed] [Google Scholar]
  97. Unger V. M., Hargrave P. A., Baldwin J. M., Schertler G. F. Arrangement of rhodopsin transmembrane alpha-helices. Nature. 1997 Sep 11;389(6647):203–206. doi: 10.1038/38316. [DOI] [PubMed] [Google Scholar]
  98. Unger V. M., Schertler G. F. Low resolution structure of bovine rhodopsin determined by electron cryo-microscopy. Biophys J. 1995 May;68(5):1776–1786. doi: 10.1016/S0006-3495(95)80354-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Valiquette M., Vu H. K., Yue S. Y., Wahlestedt C., Walker P. Involvement of Trp-284, Val-296, and Val-297 of the human delta-opioid receptor in binding of delta-selective ligands. J Biol Chem. 1996 Aug 2;271(31):18789–18796. doi: 10.1074/jbc.271.31.18789. [DOI] [PubMed] [Google Scholar]
  100. Varga E. V., Li X., Stropova D., Zalewska T., Landsman R. S., Knapp R. J., Malatynska E., Kawai K., Mizusura A., Nagase H. The third extracellular loop of the human delta-opioid receptor determines the selectivity of delta-opioid agonists. Mol Pharmacol. 1996 Dec;50(6):1619–1624. [PubMed] [Google Scholar]
  101. Wang C. D., Buck M. A., Fraser C. M. Site-directed mutagenesis of alpha 2A-adrenergic receptors: identification of amino acids involved in ligand binding and receptor activation by agonists. Mol Pharmacol. 1991 Aug;40(2):168–179. [PubMed] [Google Scholar]
  102. Wang C. D., Gallaher T. K., Shih J. C. Site-directed mutagenesis of the serotonin 5-hydroxytrypamine2 receptor: identification of amino acids necessary for ligand binding and receptor activation. Mol Pharmacol. 1993 Jun;43(6):931–940. [PubMed] [Google Scholar]
  103. Wang J. B., Johnson P. S., Wu J. M., Wang W. F., Uhl G. R. Human kappa opiate receptor second extracellular loop elevates dynorphin's affinity for human mu/kappa chimeras. J Biol Chem. 1994 Oct 21;269(42):25966–25969. [PubMed] [Google Scholar]
  104. Wang W. W., Shahrestanifar M., Jin J., Howells R. D. Studies on mu and delta opioid receptor selectivity utilizing chimeric and site-mutagenized receptors. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12436–12440. doi: 10.1073/pnas.92.26.12436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Wess J., Gdula D., Brann M. R. Site-directed mutagenesis of the m3 muscarinic receptor: identification of a series of threonine and tyrosine residues involved in agonist but not antagonist binding. EMBO J. 1991 Dec;10(12):3729–3734. doi: 10.1002/j.1460-2075.1991.tb04941.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Wilkes B. C., Schiller P. W. Comparative conformational analysis of [D-Pen2,D-Pen5]enkephalin (DPDPE): a molecular mechanics study. J Comput Aided Mol Des. 1991 Aug;5(4):293–302. doi: 10.1007/BF00126664. [DOI] [PubMed] [Google Scholar]
  107. Wong S. K., Slaughter C., Ruoho A. E., Ross E. M. The catecholamine binding site of the beta-adrenergic receptor is formed by juxtaposed membrane-spanning domains. J Biol Chem. 1988 Jun 15;263(17):7925–7928. [PubMed] [Google Scholar]
  108. Xue J. C., Chen C., Zhu J., Kunapuli S. P., de Riel J. K., Yu L., Liu-Chen L. Y. The third extracellular loop of the mu opioid receptor is important for agonist selectivity. J Biol Chem. 1995 Jun 2;270(22):12977–12979. [PubMed] [Google Scholar]
  109. Xue J. C., Chen C., Zhu J., Kunapuli S., DeRiel J. K., Yu L., Liu-Chen L. Y. Differential binding domains of peptide and non-peptide ligands in the cloned rat kappa opioid receptor. J Biol Chem. 1994 Dec 2;269(48):30195–30199. [PubMed] [Google Scholar]
  110. Yu H., Kono M., McKee T. D., Oprian D. D. A general method for mapping tertiary contacts between amino acid residues in membrane-embedded proteins. Biochemistry. 1995 Nov 21;34(46):14963–14969. doi: 10.1021/bi00046a002. [DOI] [PubMed] [Google Scholar]
  111. Zaki P. A., Bilsky E. J., Vanderah T. W., Lai J., Evans C. J., Porreca F. Opioid receptor types and subtypes: the delta receptor as a model. Annu Rev Pharmacol Toxicol. 1996;36:379–401. doi: 10.1146/annurev.pa.36.040196.002115. [DOI] [PubMed] [Google Scholar]
  112. Zhou W., Flanagan C., Ballesteros J. A., Konvicka K., Davidson J. S., Weinstein H., Millar R. P., Sealfon S. C. A reciprocal mutation supports helix 2 and helix 7 proximity in the gonadotropin-releasing hormone receptor. Mol Pharmacol. 1994 Feb;45(2):165–170. [PubMed] [Google Scholar]
  113. Zhu J., Xue J. C., Law P. Y., Claude P. A., Luo L. Y., Yin J., Chen C., Liu-Chen L. Y. The region in the mu opioid receptor conferring selectivity for sufentanil over the delta receptor is different from that over the kappa receptor. FEBS Lett. 1996 Apr 15;384(2):198–202. doi: 10.1016/0014-5793(96)00312-2. [DOI] [PubMed] [Google Scholar]
  114. Zhu J., Yin J., Law P. Y., Claude P. A., Rice K. C., Evans C. J., Chen C., Yu L., Liu-Chen L. Y. Irreversible binding of cis-(+)-3-methylfentanyl isothiocyanate to the delta opioid receptor and determination of its binding domain. J Biol Chem. 1996 Jan 19;271(3):1430–1434. doi: 10.1074/jbc.271.3.1430. [DOI] [PubMed] [Google Scholar]
  115. Zhukovsky E. A., Robinson P. R., Oprian D. D. Changing the location of the Schiff base counterion in rhodopsin. Biochemistry. 1992 Oct 27;31(42):10400–10405. doi: 10.1021/bi00157a030. [DOI] [PubMed] [Google Scholar]
  116. de Alba E., Jiménez M. A., Rico M., Nieto J. L. Conformational investigation of designed short linear peptides able to fold into beta-hairpin structures in aqueous solution. Fold Des. 1996;1(2):133–144. doi: 10.1016/s1359-0278(96)00022-3. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES