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Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptor

Kirkpatrick, Andrea and Heo, Jiyoung and Abrol, Ravinder and Goddard, William A., III (2012) Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptor. Proceedings of the National Academy of Sciences of the United States of America, 109 (49). pp. 19988-19993. ISSN 0027-8424. PMCID PMC3523846. https://resolver.caltech.edu/CaltechAUTHORS:20130104-104903264

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Abstract

The glucagon-like peptide 1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) involved in insulin synthesis and regulation; therefore, it is an important drug target for treatment of diabetes. However, GLP1R is a member of the class B1 family of GPCRs for which there are no experimental structures. To provide a structural basis for drug design and to probe class B GPCR activation, we predicted the transmembrane (TM) bundle structure of GLP1R bound to the peptide Exendin-4 (Exe4; a GLP1R agonist on the market for treating diabetes) using the MembStruk method for scanning TM bundle conformations. We used protein–protein docking methods to combine the TM bundle with the X-ray crystal structure of the 143-aa N terminus coupled to the Exe4 peptide. This complex was subjected to 28 ns of full-solvent, full-lipid molecular dynamics. We find 14 strong polar interactions of Exe4 with GLP1R, of which 8 interactions are in the TM bundle (2 interactions confirmed by mutation studies) and 6 interactions involve the N terminus (3 interactions found in the crystal structure). We also find 10 important hydrophobic interactions, of which 4 interactions are in the TM bundle (2 interactions confirmed by mutation studies) and 6 interactions are in the N terminus (6 interactions present in the crystal structure). Thus, our predicted structure agrees with available mutagenesis studies. We suggest a number of mutation experiments to further validate our predicted structure. The structure should be useful for guiding drug design and can provide a structural basis for understanding ligand binding and receptor activation of GLP1R and other class B1 GPCRs.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1218051109 DOIArticle
http://www.pnas.org/cgi/doi/10.1073/pnas.1218051109PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523846/PubMed CentralArticle
ORCID:
AuthorORCID
Abrol, Ravinder0000-0001-7333-6793
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2012 National Academy of Sciences. Contributed by William A. Goddard III, October 18, 2012 (sent for review July 9, 2012). Published online before print November 19, 2012. The MembStruk studies by J.H. were funded by Allozyne (Ken Grabstein). The final optimization of the structure and analysis (A.K.) was funded by Sanofi-Aventis (Ken Wertman). Author contributions: A.K., J.H., R.A., and W.A.G. designed research; A.K. and J.H. performed research; and A.K., R.A., and W.A.G. wrote the paper.
Funders:
Funding AgencyGrant Number
AllozyneUNSPECIFIED
Sanofi-AventisUNSPECIFIED
Subject Keywords:protein structure prediction; incretin receptors; peptide hormones
Issue or Number:49
PubMed Central ID:PMC3523846
Record Number:CaltechAUTHORS:20130104-104903264
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130104-104903264
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:36169
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:04 Jan 2013 19:46
Last Modified:03 Oct 2019 04:35

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