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. 2000 Nov;9(11):2200–2209. doi: 10.1110/ps.9.11.2200

Three-dimensional model of the extracellular domain of the type 4a metabotropic glutamate receptor: new insights into the activation process.

A S Bessis 1, H O Bertrand 1, T Galvez 1, C De Colle 1, J P Pin 1, F Acher 1
PMCID: PMC2144486  PMID: 11152130

Abstract

Metabotropic glutamate receptors (mGluRs) belong to the family 3 of G-protein-coupled receptors. On these proteins, agonist binding on the extracellular domain leads to conformational changes in the 7-transmembrane domains required for G-protein activation. To elucidate the structural features that might be responsible for such an activation mechanism, we have generated models of the amino terminal domain (ATD) of type 4 mGluR (mGlu4R). The fold recognition search allowed the identification of three hits with a low sequence identity, but with high secondary structure conservation: leucine isoleucine valine-binding protein (LIVBP) and leucine-binding protein (LBP) as already known, and acetamide-binding protein (AmiC). These proteins are characterized by a bilobate structure in an open state for LIVBP/LBP and a closed state for AmiC, with ligand binding in the cleft. Models for both open and closed forms of mGlu4R ATD have been generated. ACPT-I (1-aminocyclopentane 1,3,4-tricarboxylic acid), a selective agonist, has been docked in the two models. In the open form, ACPT-I is only bound to lobe I through interactions with Lys74, Arg78, Ser159, and Thr182. In the closed form, ACPT-I is trapped between both lobes with additional binding to Tyr230, Asp312, Ser313, and Lys317 from lobe II. These results support the hypothesis that mGluR agonists bind a closed form of the ATDs, suggesting that such a conformation of the binding domain corresponds to the active conformation.

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Selected References

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

  1. Acher F. C., Tellier F. J., Azerad R., Brabet I. N., Fagni L., Pin J. P. Synthesis and pharmacological characterization of aminocyclopentanetricarboxylic acids: new tools to discriminate between metabotropic glutamate receptor subtypes. J Med Chem. 1997 Sep 12;40(19):3119–3129. doi: 10.1021/jm970207b. [DOI] [PubMed] [Google Scholar]
  2. Altschul S. F., Madden T. L., Schäffer A. A., Zhang J., Zhang Z., Miller W., Lipman D. J. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997 Sep 1;25(17):3389–3402. doi: 10.1093/nar/25.17.3389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Armstrong N., Sun Y., Chen G. Q., Gouaux E. Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature. 1998 Oct 29;395(6705):913–917. doi: 10.1038/27692. [DOI] [PubMed] [Google Scholar]
  4. Bessis A. S., Jullian N., Coudert E., Pin J. P., Acher F. Extended glutamate activates metabotropic receptor types 1, 2 and 4: selective features at mGluR4 binding site. Neuropharmacology. 1999 Oct;38(10):1543–1551. doi: 10.1016/s0028-3908(99)00096-9. [DOI] [PubMed] [Google Scholar]
  5. Bockaert J., Pin J. P. Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J. 1999 Apr 1;18(7):1723–1729. doi: 10.1093/emboj/18.7.1723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brown E. M., Hebert S. C. Calcium-receptor-regulated parathyroid and renal function. Bone. 1997 Apr;20(4):303–309. doi: 10.1016/s8756-3282(97)00002-1. [DOI] [PubMed] [Google Scholar]
  7. Bräuner-Osborne H., Jensen A. A., Sheppard P. O., O'Hara P., Krogsgaard-Larsen P. The agonist-binding domain of the calcium-sensing receptor is located at the amino-terminal domain. J Biol Chem. 1999 Jun 25;274(26):18382–18386. doi: 10.1074/jbc.274.26.18382. [DOI] [PubMed] [Google Scholar]
  8. Chamberlain D., O'Hara B. P., Wilson S. A., Pearl L. H., Perkins S. J. Oligomerization of the amide sensor protein AmiC by x-ray and neutron scattering and molecular modeling. Biochemistry. 1997 Jul 1;36(26):8020–8029. doi: 10.1021/bi9703251. [DOI] [PubMed] [Google Scholar]
  9. Conn P. J., Pin J. P. Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol. 1997;37:205–237. doi: 10.1146/annurev.pharmtox.37.1.205. [DOI] [PubMed] [Google Scholar]
  10. Costantino G., Macchiarulo A., Pellicciari R. Modeling of amino-terminal domains of group I metabotropic glutamate receptors: structural motifs affecting ligand selectivity. J Med Chem. 1999 Dec 30;42(26):5390–5401. doi: 10.1021/jm990353c. [DOI] [PubMed] [Google Scholar]
  11. Costantino G., Pellicciari R. Homology modeling of metabotropic glutamate receptors. (mGluRs) structural motifs affecting binding modes and pharmacological profile of mGluR1 agonists and competitive antagonists. J Med Chem. 1996 Sep 27;39(20):3998–4006. doi: 10.1021/jm9601718. [DOI] [PubMed] [Google Scholar]
  12. De Colle C., Bessis A. S., Bockaert J., Acher F., Pin J. P. Pharmacological characterization of the rat metabotropic glutamate receptor type 8a revealed strong similarities and slight differences with the type 4a receptor. Eur J Pharmacol. 2000 Apr 7;394(1):17–26. doi: 10.1016/s0014-2999(00)00113-8. [DOI] [PubMed] [Google Scholar]
  13. Dougherty D. A. Cation-pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp. Science. 1996 Jan 12;271(5246):163–168. doi: 10.1126/science.271.5246.163. [DOI] [PubMed] [Google Scholar]
  14. Duvoisin R. M., Zhang C., Ramonell K. A novel metabotropic glutamate receptor expressed in the retina and olfactory bulb. J Neurosci. 1995 Apr;15(4):3075–3083. doi: 10.1523/JNEUROSCI.15-04-03075.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fischer D., Eisenberg D. Protein fold recognition using sequence-derived predictions. Protein Sci. 1996 May;5(5):947–955. doi: 10.1002/pro.5560050516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Galvez T., Parmentier M. L., Joly C., Malitschek B., Kaupmann K., Kuhn R., Bittiger H., Froestl W., Bettler B., Pin J. P. Mutagenesis and modeling of the GABAB receptor extracellular domain support a venus flytrap mechanism for ligand binding. J Biol Chem. 1999 May 7;274(19):13362–13369. doi: 10.1074/jbc.274.19.13362. [DOI] [PubMed] [Google Scholar]
  17. Gomeza J., Joly C., Kuhn R., Knöpfel T., Bockaert J., Pin J. P. The second intracellular loop of metabotropic glutamate receptor 1 cooperates with the other intracellular domains to control coupling to G-proteins. J Biol Chem. 1996 Jan 26;271(4):2199–2205. doi: 10.1074/jbc.271.4.2199. [DOI] [PubMed] [Google Scholar]
  18. Hampson D. R., Huang X. P., Pekhletski R., Peltekova V., Hornby G., Thomsen C., Thøgersen H. Probing the ligand-binding domain of the mGluR4 subtype of metabotropic glutamate receptor. J Biol Chem. 1999 Nov 19;274(47):33488–33495. doi: 10.1074/jbc.274.47.33488. [DOI] [PubMed] [Google Scholar]
  19. Han G., Hampson D. R. Ligand binding to the amino-terminal domain of the mGluR4 subtype of metabotropic glutamate receptor. J Biol Chem. 1999 Apr 9;274(15):10008–10013. doi: 10.1074/jbc.274.15.10008. [DOI] [PubMed] [Google Scholar]
  20. Jullian N., Brabet I., Pin J. P., Acher F. C. Agonist selectivity of mGluR1 and mGluR2 metabotropic receptors: a different environment but similar recognition of an extended glutamate conformation. J Med Chem. 1999 May 6;42(9):1546–1555. doi: 10.1021/jm980571q. [DOI] [PubMed] [Google Scholar]
  21. King R. D., Sternberg M. J. Identification and application of the concepts important for accurate and reliable protein secondary structure prediction. Protein Sci. 1996 Nov;5(11):2298–2310. doi: 10.1002/pro.5560051116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lampinen M., Pentikäinen O., Johnson M. S., Keinänen K. AMPA receptors and bacterial periplasmic amino acid-binding proteins share the ionic mechanism of ligand recognition. EMBO J. 1998 Aug 17;17(16):4704–4711. doi: 10.1093/emboj/17.16.4704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lüthy R., Bowie J. U., Eisenberg D. Assessment of protein models with three-dimensional profiles. Nature. 1992 Mar 5;356(6364):83–85. doi: 10.1038/356083a0. [DOI] [PubMed] [Google Scholar]
  24. O'Hara B. P., Norman R. A., Wan P. T., Roe S. M., Barrett T. E., Drew R. E., Pearl L. H. Crystal structure and induction mechanism of AmiC-AmiR: a ligand-regulated transcription antitermination complex. EMBO J. 1999 Oct 1;18(19):5175–5186. doi: 10.1093/emboj/18.19.5175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. O'Hara P. J., Sheppard P. O., Thøgersen H., Venezia D., Haldeman B. A., McGrane V., Houamed K. M., Thomsen C., Gilbert T. L., Mulvihill E. R. The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins. Neuron. 1993 Jul;11(1):41–52. doi: 10.1016/0896-6273(93)90269-w. [DOI] [PubMed] [Google Scholar]
  26. Okamoto T., Sekiyama N., Otsu M., Shimada Y., Sato A., Nakanishi S., Jingami H. Expression and purification of the extracellular ligand binding region of metabotropic glutamate receptor subtype 1. J Biol Chem. 1998 May 22;273(21):13089–13096. doi: 10.1074/jbc.273.21.13089. [DOI] [PubMed] [Google Scholar]
  27. Olah G. A., Trakhanov S., Trewhella J., Quiocho F. A. Leucine/isoleucine/valine-binding protein contracts upon binding of ligand. J Biol Chem. 1993 Aug 5;268(22):16241–16247. [PubMed] [Google Scholar]
  28. Pearl L., O'Hara B., Drew R., Wilson S. Crystal structure of AmiC: the controller of transcription antitermination in the amidase operon of Pseudomonas aeruginosa. EMBO J. 1994 Dec 15;13(24):5810–5817. doi: 10.1002/j.1460-2075.1994.tb06924.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Pearson W. R., Lipman D. J. Improved tools for biological sequence comparison. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2444–2448. doi: 10.1073/pnas.85.8.2444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pin J. P., De Colle C., Bessis A. S., Acher F. New perspectives for the development of selective metabotropic glutamate receptor ligands. Eur J Pharmacol. 1999 Jun 30;375(1-3):277–294. doi: 10.1016/s0014-2999(99)00258-7. [DOI] [PubMed] [Google Scholar]
  31. Pin J. P., Joly C., Heinemann S. F., Bockaert J. Domains involved in the specificity of G protein activation in phospholipase C-coupled metabotropic glutamate receptors. EMBO J. 1994 Jan 15;13(2):342–348. doi: 10.1002/j.1460-2075.1994.tb06267.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Quiocho F. A., Ledvina P. S. Atomic structure and specificity of bacterial periplasmic receptors for active transport and chemotaxis: variation of common themes. Mol Microbiol. 1996 Apr;20(1):17–25. doi: 10.1111/j.1365-2958.1996.tb02484.x. [DOI] [PubMed] [Google Scholar]
  33. Ray K., Hauschild B. C., Steinbach P. J., Goldsmith P. K., Hauache O., Spiegel A. M. Identification of the cysteine residues in the amino-terminal extracellular domain of the human Ca(2+) receptor critical for dimerization. Implications for function of monomeric Ca(2+) receptor. J Biol Chem. 1999 Sep 24;274(39):27642–27650. doi: 10.1074/jbc.274.39.27642. [DOI] [PubMed] [Google Scholar]
  34. Rost B., Sander C. Prediction of protein secondary structure at better than 70% accuracy. J Mol Biol. 1993 Jul 20;232(2):584–599. doi: 10.1006/jmbi.1993.1413. [DOI] [PubMed] [Google Scholar]
  35. Sack J. S., Saper M. A., Quiocho F. A. Periplasmic binding protein structure and function. Refined X-ray structures of the leucine/isoleucine/valine-binding protein and its complex with leucine. J Mol Biol. 1989 Mar 5;206(1):171–191. doi: 10.1016/0022-2836(89)90531-7. [DOI] [PubMed] [Google Scholar]
  36. Sack J. S., Trakhanov S. D., Tsigannik I. H., Quiocho F. A. Structure of the L-leucine-binding protein refined at 2.4 A resolution and comparison with the Leu/Ile/Val-binding protein structure. J Mol Biol. 1989 Mar 5;206(1):193–207. doi: 10.1016/0022-2836(89)90532-9. [DOI] [PubMed] [Google Scholar]
  37. Sali A., Blundell T. L. Definition of general topological equivalence in protein structures. A procedure involving comparison of properties and relationships through simulated annealing and dynamic programming. J Mol Biol. 1990 Mar 20;212(2):403–428. doi: 10.1016/0022-2836(90)90134-8. [DOI] [PubMed] [Google Scholar]
  38. Schoepp D. D., Jane D. E., Monn J. A. Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology. 1999 Oct;38(10):1431–1476. doi: 10.1016/s0028-3908(99)00092-1. [DOI] [PubMed] [Google Scholar]
  39. Stern-Bach Y., Bettler B., Hartley M., Sheppard P. O., O'Hara P. J., Heinemann S. F. Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid-binding proteins. Neuron. 1994 Dec;13(6):1345–1357. doi: 10.1016/0896-6273(94)90420-0. [DOI] [PubMed] [Google Scholar]
  40. Takahashi K., Tsuchida K., Tanabe Y., Masu M., Nakanishi S. Role of the large extracellular domain of metabotropic glutamate receptors in agonist selectivity determination. J Biol Chem. 1993 Sep 15;268(26):19341–19345. [PubMed] [Google Scholar]
  41. Tam R., Saier M. H., Jr Structural, functional, and evolutionary relationships among extracellular solute-binding receptors of bacteria. Microbiol Rev. 1993 Jun;57(2):320–346. doi: 10.1128/mr.57.2.320-346.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Thompson J. D., Higgins D. G., Gibson T. J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994 Nov 11;22(22):4673–4680. doi: 10.1093/nar/22.22.4673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Trakhanov S., Quiocho F. A. Influence of divalent cations in protein crystallization. Protein Sci. 1995 Sep;4(9):1914–1919. doi: 10.1002/pro.5560040925. [DOI] [PMC free article] [PubMed] [Google Scholar]

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