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Title: Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40

Abstract

Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40–MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1404966
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Structural & Molecular Biology; Journal Volume: 24; Journal Issue: 7
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Lu, Jun, Byrne, Noel, Wang, John, Bricogne, Gerard, Brown, Frank K., Chobanian, Harry R., Colletti, Steven L., Di Salvo, Jerry, Thomas-Fowlkes, Brande, Guo, Yan, Hall, Dawn L., Hadix, Jennifer, Hastings, Nicholas B., Hermes, Jeffrey D., Ho, Thu, Howard, Andrew D., Josien, Hubert, Kornienko, Maria, Lumb, Kevin J., Miller, Michael W., Patel, Sangita B., Pio, Barbara, Plummer, Christopher W., Sherborne, Bradley S., Sheth, Payal, Souza, Sarah, Tummala, Srivanya, Vonrhein, Clemens, Webb, Maria, Allen, Samantha J., Johnston, Jennifer M., Weinglass, Adam B., Sharma, Sujata, and Soisson, Stephen M. Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. United States: N. p., 2017. Web. doi:10.1038/nsmb.3417.
Lu, Jun, Byrne, Noel, Wang, John, Bricogne, Gerard, Brown, Frank K., Chobanian, Harry R., Colletti, Steven L., Di Salvo, Jerry, Thomas-Fowlkes, Brande, Guo, Yan, Hall, Dawn L., Hadix, Jennifer, Hastings, Nicholas B., Hermes, Jeffrey D., Ho, Thu, Howard, Andrew D., Josien, Hubert, Kornienko, Maria, Lumb, Kevin J., Miller, Michael W., Patel, Sangita B., Pio, Barbara, Plummer, Christopher W., Sherborne, Bradley S., Sheth, Payal, Souza, Sarah, Tummala, Srivanya, Vonrhein, Clemens, Webb, Maria, Allen, Samantha J., Johnston, Jennifer M., Weinglass, Adam B., Sharma, Sujata, & Soisson, Stephen M. Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. United States. doi:10.1038/nsmb.3417.
Lu, Jun, Byrne, Noel, Wang, John, Bricogne, Gerard, Brown, Frank K., Chobanian, Harry R., Colletti, Steven L., Di Salvo, Jerry, Thomas-Fowlkes, Brande, Guo, Yan, Hall, Dawn L., Hadix, Jennifer, Hastings, Nicholas B., Hermes, Jeffrey D., Ho, Thu, Howard, Andrew D., Josien, Hubert, Kornienko, Maria, Lumb, Kevin J., Miller, Michael W., Patel, Sangita B., Pio, Barbara, Plummer, Christopher W., Sherborne, Bradley S., Sheth, Payal, Souza, Sarah, Tummala, Srivanya, Vonrhein, Clemens, Webb, Maria, Allen, Samantha J., Johnston, Jennifer M., Weinglass, Adam B., Sharma, Sujata, and Soisson, Stephen M. 2017. "Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40". United States. doi:10.1038/nsmb.3417.
@article{osti_1404966,
title = {Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40},
author = {Lu, Jun and Byrne, Noel and Wang, John and Bricogne, Gerard and Brown, Frank K. and Chobanian, Harry R. and Colletti, Steven L. and Di Salvo, Jerry and Thomas-Fowlkes, Brande and Guo, Yan and Hall, Dawn L. and Hadix, Jennifer and Hastings, Nicholas B. and Hermes, Jeffrey D. and Ho, Thu and Howard, Andrew D. and Josien, Hubert and Kornienko, Maria and Lumb, Kevin J. and Miller, Michael W. and Patel, Sangita B. and Pio, Barbara and Plummer, Christopher W. and Sherborne, Bradley S. and Sheth, Payal and Souza, Sarah and Tummala, Srivanya and Vonrhein, Clemens and Webb, Maria and Allen, Samantha J. and Johnston, Jennifer M. and Weinglass, Adam B. and Sharma, Sujata and Soisson, Stephen M.},
abstractNote = {Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40–MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.},
doi = {10.1038/nsmb.3417},
journal = {Nature Structural & Molecular Biology},
number = 7,
volume = 24,
place = {United States},
year = 2017,
month = 6
}