Skip to main content
NCBI home page
Biophysical Journal logoLink to Biophysical Journal
. 2000 Nov;79(5):2754–2760. doi: 10.1016/S0006-3495(00)76514-3

Serine and threonine residues bend alpha-helices in the chi(1) = g(-) conformation.

J A Ballesteros 1, X Deupi 1, M Olivella 1, E E Haaksma 1, L Pardo 1
PMCID: PMC1301156  PMID: 11053148

Abstract

The relationship between the Ser, Thr, and Cys side-chain conformation (chi(1) = g(-), t, g(+)) and the main-chain conformation (phi and psi angles) has been studied in a selection of protein structures that contain alpha-helices. The statistical results show that the g(-) conformation of both Ser and Thr residues decreases their phi angles and increases their psi angles relative to Ala, used as a control. The additional hydrogen bond formed between the O(gamma) atom of Ser and Thr and the i-3 or i-4 peptide carbonyl oxygen induces or stabilizes a bending angle in the helix 3-4 degrees larger than for Ala. This is of particular significance for membrane proteins. Incorporation of this small bending angle in the transmembrane alpha-helix at one side of the cell membrane results in a significant displacement of the residues located at the other side of the membrane. We hypothesize that local alterations of the rotamer configurations of these Ser and Thr residues may result in significant conformational changes across transmembrane helices, and thus participate in the molecular mechanisms underlying transmembrane signaling. This finding has provided the structural basis to understand the experimentally observed influence of Ser residues on the conformational equilibrium between inactive and active states of the receptor, in the neurotransmitter subfamily of G protein-coupled receptors.

Full Text

The Full Text of this article is available as a PDF (414.8 KB).

Selected References

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

  1. Ambrosio C., Molinari P., Cotecchia S., Costa T. Catechol-binding serines of beta(2)-adrenergic receptors control the equilibrium between active and inactive receptor states. Mol Pharmacol. 2000 Jan;57(1):198–210. [PubMed] [Google Scholar]
  2. 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]
  3. 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]
  4. Blundell T., Barlow D., Borkakoti N., Thornton J. Solvent-induced distortions and the curvature of alpha-helices. Nature. 1983 Nov 17;306(5940):281–283. doi: 10.1038/306281a0. [DOI] [PubMed] [Google Scholar]
  5. Bond R. A., Leff P., Johnson T. D., Milano C. A., Rockman H. A., McMinn T. R., Apparsundaram S., Hyek M. F., Kenakin T. P., Allen L. F. Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the beta 2-adrenoceptor. Nature. 1995 Mar 16;374(6519):272–276. doi: 10.1038/374272a0. [DOI] [PubMed] [Google Scholar]
  6. Doyle D. A., Morais Cabral J., Pfuetzner R. A., Kuo A., Gulbis J. M., Cohen S. L., Chait B. T., MacKinnon R. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science. 1998 Apr 3;280(5360):69–77. doi: 10.1126/science.280.5360.69. [DOI] [PubMed] [Google Scholar]
  7. Gether U., Ballesteros J. A., Seifert R., Sanders-Bush E., Weinstein H., Kobilka B. K. Structural instability of a constitutively active G protein-coupled receptor. Agonist-independent activation due to conformational flexibility. J Biol Chem. 1997 Jan 31;272(5):2587–2590. doi: 10.1074/jbc.272.5.2587. [DOI] [PubMed] [Google Scholar]
  8. Gether U., Kobilka B. K. G protein-coupled receptors. II. Mechanism of agonist activation. J Biol Chem. 1998 Jul 17;273(29):17979–17982. doi: 10.1074/jbc.273.29.17979. [DOI] [PubMed] [Google Scholar]
  9. Gether U., Lin S., Ghanouni P., Ballesteros J. A., Weinstein H., Kobilka B. K. Agonists induce conformational changes in transmembrane domains III and VI of the beta2 adrenoceptor. EMBO J. 1997 Nov 17;16(22):6737–6747. doi: 10.1093/emboj/16.22.6737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gray T. M., Matthews B. W. Intrahelical hydrogen bonding of serine, threonine and cysteine residues within alpha-helices and its relevance to membrane-bound proteins. J Mol Biol. 1984 May 5;175(1):75–81. doi: 10.1016/0022-2836(84)90446-7. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Lefkowitz R. J., Cotecchia S., Samama P., Costa T. Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins. Trends Pharmacol Sci. 1993 Aug;14(8):303–307. doi: 10.1016/0165-6147(93)90048-O. [DOI] [PubMed] [Google Scholar]
  13. McGregor M. J., Islam S. A., Sternberg M. J. Analysis of the relationship between side-chain conformation and secondary structure in globular proteins. J Mol Biol. 1987 Nov 20;198(2):295–310. doi: 10.1016/0022-2836(87)90314-7. [DOI] [PubMed] [Google Scholar]
  14. Monné M., Hermansson M., von Heijne G. A turn propensity scale for transmembrane helices. J Mol Biol. 1999 Apr 23;288(1):141–145. doi: 10.1006/jmbi.1999.2657. [DOI] [PubMed] [Google Scholar]
  15. Pardo L., Campillo M., Giraldo J. The effect of the molecular mechanism of G protein-coupled receptor activation on the process of signal transduction. Eur J Pharmacol. 1997 Sep 17;335(1):73–87. doi: 10.1016/s0014-2999(97)01170-9. [DOI] [PubMed] [Google Scholar]
  16. Ri Y., Ballesteros J. A., Abrams C. K., Oh S., Verselis V. K., Weinstein H., Bargiello T. A. The role of a conserved proline residue in mediating conformational changes associated with voltage gating of Cx32 gap junctions. Biophys J. 1999 Jun;76(6):2887–2898. doi: 10.1016/S0006-3495(99)77444-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Samama P., Cotecchia S., Costa T., Lefkowitz R. J. A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. J Biol Chem. 1993 Mar 5;268(7):4625–4636. [PubMed] [Google Scholar]
  18. Senes A., Gerstein M., Engelman D. M. Statistical analysis of amino acid patterns in transmembrane helices: the GxxxG motif occurs frequently and in association with beta-branched residues at neighboring positions. J Mol Biol. 2000 Feb 25;296(3):921–936. doi: 10.1006/jmbi.1999.3488. [DOI] [PubMed] [Google Scholar]
  19. Stowell M. H., McPhillips T. M., Rees D. C., Soltis S. M., Abresch E., Feher G. Light-induced structural changes in photosynthetic reaction center: implications for mechanism of electron-proton transfer. Science. 1997 May 2;276(5313):812–816. doi: 10.1126/science.276.5313.812. [DOI] [PubMed] [Google Scholar]
  20. Tsukihara T., Aoyama H., Yamashita E., Tomizaki T., Yamaguchi H., Shinzawa-Itoh K., Nakashima R., Yaono R., Yoshikawa S. The whole structure of the 13-subunit oxidized cytochrome c oxidase at 2.8 A. Science. 1996 May 24;272(5265):1136–1144. doi: 10.1126/science.272.5265.1136. [DOI] [PubMed] [Google Scholar]
  21. 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]

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

RESOURCES