Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptor
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.
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.Attached Files
Published - PNAS-2012-Kirkpatrick-19988-93.pdf
Supplemental Material - pnas.201218051SI.pdf
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Additional details
- PMCID
- PMC3523846
- Eprint ID
- 36169
- Resolver ID
- CaltechAUTHORS:20130104-104903264
- Allozyne
- Sanofi-Aventis
- Created
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2013-01-04Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field