Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40
Crystal structures of hGPR40, a target for treatment of type 2 diabetes, bound to a partial and an allosteric agonist explain the binding cooperativity between these ligands and present new opportunities for structure-guided drug design. Clinical studies indicate that partial agonists of the G-prote...
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| Veröffentlicht in: | Nature structural & molecular biology 2017-07, Vol.24 (7), p.570-577 |
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| creator | 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 |
| description | Crystal structures of hGPR40, a target for treatment of type 2 diabetes, bound to a partial and an allosteric agonist explain the binding cooperativity between these ligands and present new opportunities for structure-guided drug design.
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_str_mv | 10.1038/nsmb.3417 |
| format | Article |
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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.</description><identifier>ISSN: 1545-9993</identifier><identifier>EISSN: 1545-9985</identifier><identifier>DOI: 10.1038/nsmb.3417</identifier><identifier>PMID: 28581512</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>60 APPLIED LIFE SCIENCES ; 631/154 ; 631/443/319/1642 ; 631/45/612/194 ; 631/535/1266 ; Activation analysis ; Allosteric properties ; Allosteric Regulation ; BASIC BIOLOGICAL SCIENCES ; Binding Sites ; Biochemistry ; Biological Microscopy ; Bundling ; Cell receptors ; Cooperativity ; Crystal structure ; Crystallography, X-Ray ; Diabetes mellitus ; Fatty acids ; Glucose ; Helices ; Humans ; Insulin ; Insulin secretion ; Life Sciences ; Ligands ; Ligands (Biochemistry) ; Lipids ; Membrane Biology ; Models, Molecular ; Molecular structure ; Properties ; Protein Binding ; Protein Conformation ; Protein Structure ; Proteins ; Receptors, G-Protein-Coupled - agonists ; Receptors, G-Protein-Coupled - chemistry ; Secretion ; Testing</subject><ispartof>Nature structural & molecular biology, 2017-07, Vol.24 (7), p.570-577</ispartof><rights>Springer Nature America, Inc. 2017</rights><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 2017</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c542t-2f449f88dfd74b7c08abad061d08ac1bd2ffb6e3f8872132bb1d75b2cb7f09e83</citedby><cites>FETCH-LOGICAL-c542t-2f449f88dfd74b7c08abad061d08ac1bd2ffb6e3f8872132bb1d75b2cb7f09e83</cites><orcidid>0000-0003-2778-9956 ; 0000000327789956</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nsmb.3417$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nsmb.3417$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28581512$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1404966$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Lu, Jun</creatorcontrib><creatorcontrib>Byrne, Noel</creatorcontrib><creatorcontrib>Wang, John</creatorcontrib><creatorcontrib>Bricogne, Gerard</creatorcontrib><creatorcontrib>Brown, Frank K</creatorcontrib><creatorcontrib>Chobanian, Harry R</creatorcontrib><creatorcontrib>Colletti, Steven L</creatorcontrib><creatorcontrib>Di Salvo, Jerry</creatorcontrib><creatorcontrib>Thomas-Fowlkes, Brande</creatorcontrib><creatorcontrib>Guo, Yan</creatorcontrib><creatorcontrib>Hall, Dawn L</creatorcontrib><creatorcontrib>Hadix, Jennifer</creatorcontrib><creatorcontrib>Hastings, Nicholas B</creatorcontrib><creatorcontrib>Hermes, Jeffrey D</creatorcontrib><creatorcontrib>Ho, Thu</creatorcontrib><creatorcontrib>Howard, Andrew D</creatorcontrib><creatorcontrib>Josien, Hubert</creatorcontrib><creatorcontrib>Kornienko, Maria</creatorcontrib><creatorcontrib>Lumb, Kevin J</creatorcontrib><creatorcontrib>Miller, Michael W</creatorcontrib><creatorcontrib>Patel, Sangita B</creatorcontrib><creatorcontrib>Pio, Barbara</creatorcontrib><creatorcontrib>Plummer, Christopher W</creatorcontrib><creatorcontrib>Sherborne, Bradley S</creatorcontrib><creatorcontrib>Sheth, Payal</creatorcontrib><creatorcontrib>Souza, Sarah</creatorcontrib><creatorcontrib>Tummala, Srivanya</creatorcontrib><creatorcontrib>Vonrhein, Clemens</creatorcontrib><creatorcontrib>Webb, Maria</creatorcontrib><creatorcontrib>Allen, Samantha J</creatorcontrib><creatorcontrib>Johnston, Jennifer M</creatorcontrib><creatorcontrib>Weinglass, Adam B</creatorcontrib><creatorcontrib>Sharma, Sujata</creatorcontrib><creatorcontrib>Soisson, Stephen M</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40</title><title>Nature structural & molecular biology</title><addtitle>Nat Struct Mol Biol</addtitle><addtitle>Nat Struct Mol Biol</addtitle><description>Crystal structures of hGPR40, a target for treatment of type 2 diabetes, bound to a partial and an allosteric agonist explain the binding cooperativity between these ligands and present new opportunities for structure-guided drug design.
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.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>631/154</subject><subject>631/443/319/1642</subject><subject>631/45/612/194</subject><subject>631/535/1266</subject><subject>Activation analysis</subject><subject>Allosteric properties</subject><subject>Allosteric Regulation</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Binding Sites</subject><subject>Biochemistry</subject><subject>Biological Microscopy</subject><subject>Bundling</subject><subject>Cell receptors</subject><subject>Cooperativity</subject><subject>Crystal structure</subject><subject>Crystallography, X-Ray</subject><subject>Diabetes mellitus</subject><subject>Fatty acids</subject><subject>Glucose</subject><subject>Helices</subject><subject>Humans</subject><subject>Insulin</subject><subject>Insulin secretion</subject><subject>Life 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chemistry</subject><subject>Secretion</subject><subject>Testing</subject><issn>1545-9993</issn><issn>1545-9985</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptktFqFTEQhhdRbK1e-AKy6I0K55jsJpvkshSthYLS6nVMspPTlN3NaZIV-_bOemq1WgLJMPPNnxn4q-o5JWtKWvluyqNdt4yKB9U-5YyvlJL84W2s2r3qSc6XhDSci_ZxtddILimnzX717byk2ZU5maG2Jodc-5jqcgG1i3ELyZTwHWozDDEXSMHVxmEGs3Gqo_8F-gR4mVKusRj6OoGDbUGV489njDytHnkzZHh28x5UXz-8_3L0cXX66fjk6PB05ThryqrxjCkvZe97waxwRBpretLRHiNHbd94bztoERENbRtraS-4bZwVniiQ7UH1cqeLgwadXSjgLlycJnBFU0aY6jqEXu-gbYpXM-Six5AdDIOZIM5ZU4U_tlK1i96rf9DLOKcJV0CKdkIppsgfamMG0GHysSTjFlF9yJSQgnLFkVrfQ-HpYQw4I_iA-TsNb-40IFPgR9mYOWd9cn52L-tSzDmB19sURpOuNSV6sYde7KEXeyD74map2Y7Q35K__YDA2x2QsTRtIP219X9qPwGxI8Gi</recordid><startdate>20170701</startdate><enddate>20170701</enddate><creator>Lu, 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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Research Library China</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><jtitle>Nature structural & molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lu, Jun</au><au>Byrne, Noel</au><au>Wang, John</au><au>Bricogne, Gerard</au><au>Brown, Frank K</au><au>Chobanian, Harry R</au><au>Colletti, Steven L</au><au>Di Salvo, Jerry</au><au>Thomas-Fowlkes, Brande</au><au>Guo, Yan</au><au>Hall, Dawn L</au><au>Hadix, Jennifer</au><au>Hastings, Nicholas B</au><au>Hermes, Jeffrey D</au><au>Ho, Thu</au><au>Howard, Andrew D</au><au>Josien, Hubert</au><au>Kornienko, Maria</au><au>Lumb, Kevin J</au><au>Miller, Michael W</au><au>Patel, Sangita B</au><au>Pio, Barbara</au><au>Plummer, Christopher W</au><au>Sherborne, Bradley S</au><au>Sheth, Payal</au><au>Souza, Sarah</au><au>Tummala, Srivanya</au><au>Vonrhein, Clemens</au><au>Webb, Maria</au><au>Allen, Samantha J</au><au>Johnston, Jennifer M</au><au>Weinglass, Adam B</au><au>Sharma, Sujata</au><au>Soisson, Stephen M</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40</atitle><jtitle>Nature structural & molecular biology</jtitle><stitle>Nat Struct Mol Biol</stitle><addtitle>Nat Struct Mol Biol</addtitle><date>2017-07-01</date><risdate>2017</risdate><volume>24</volume><issue>7</issue><spage>570</spage><epage>577</epage><pages>570-577</pages><issn>1545-9993</issn><eissn>1545-9985</eissn><abstract>Crystal structures of hGPR40, a target for treatment of type 2 diabetes, bound to a partial and an allosteric agonist explain the binding cooperativity between these ligands and present new opportunities for structure-guided drug design.
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.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>28581512</pmid><doi>10.1038/nsmb.3417</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-2778-9956</orcidid><orcidid>https://orcid.org/0000000327789956</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1545-9993 |
| ispartof | Nature structural & molecular biology, 2017-07, Vol.24 (7), p.570-577 |
| issn | 1545-9993 1545-9985 |
| language | eng |
| recordid | cdi_osti_scitechconnect_1404966 |
| source | MEDLINE; Nature; SpringerLink Journals - AutoHoldings |
| subjects | 60 APPLIED LIFE SCIENCES 631/154 631/443/319/1642 631/45/612/194 631/535/1266 Activation analysis Allosteric properties Allosteric Regulation BASIC BIOLOGICAL SCIENCES Binding Sites Biochemistry Biological Microscopy Bundling Cell receptors Cooperativity Crystal structure Crystallography, X-Ray Diabetes mellitus Fatty acids Glucose Helices Humans Insulin Insulin secretion Life Sciences Ligands Ligands (Biochemistry) Lipids Membrane Biology Models, Molecular Molecular structure Properties Protein Binding Protein Conformation Protein Structure Proteins Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - chemistry Secretion Testing |
| title | Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40 |
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