5kw2

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==The extra-helical binding site of GPR40 and the structural basis for allosteric agonism and incretin stimulation==
==The extra-helical binding site of GPR40 and the structural basis for allosteric agonism and incretin stimulation==
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<StructureSection load='5kw2' size='340' side='right' caption='[[5kw2]], [[Resolution|resolution]] 2.76&Aring;' scene=''>
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<StructureSection load='5kw2' size='340' side='right'caption='[[5kw2]], [[Resolution|resolution]] 2.76&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5kw2]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KW2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KW2 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5kw2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_virus_T4 Escherichia virus T4] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KW2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KW2 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6XQ:(3~{S})-3-cyclopropyl-3-[2-[1-[2-[2,2-dimethylpropyl-(6-methylpyridin-2-yl)carbamoyl]-5-methoxy-phenyl]piperidin-4-yl]-1-benzofuran-6-yl]propanoic+acid'>6XQ</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.76&#8491;</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Lysozyme Lysozyme], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.17 3.2.1.17] </span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6XQ:(3~{S})-3-cyclopropyl-3-[2-[1-[2-[2,2-dimethylpropyl-(6-methylpyridin-2-yl)carbamoyl]-5-methoxy-phenyl]piperidin-4-yl]-1-benzofuran-6-yl]propanoic+acid'>6XQ</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5kw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kw2 OCA], [http://pdbe.org/5kw2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kw2 RCSB], [http://www.ebi.ac.uk/pdbsum/5kw2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kw2 ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5kw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kw2 OCA], [https://pdbe.org/5kw2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kw2 RCSB], [https://www.ebi.ac.uk/pdbsum/5kw2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kw2 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/FFAR1_HUMAN FFAR1_HUMAN]] Receptor for medium and long chain saturated and unsaturated fatty acids. Binding of the ligand increase intracellular calcium concentration and amplify glucose-stimulated insulin secretion. The activity of this receptor is mediated by G-proteins that activate phospholipase C. Seems to act through a G(q) and G(i)-mediated pathway.<ref>PMID:12496284</ref>
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[https://www.uniprot.org/uniprot/ENLYS_BPT4 ENLYS_BPT4] Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.<ref>PMID:22389108</ref> [https://www.uniprot.org/uniprot/FFAR1_HUMAN FFAR1_HUMAN] Receptor for medium and long chain saturated and unsaturated fatty acids. Binding of the ligand increase intracellular calcium concentration and amplify glucose-stimulated insulin secretion. The activity of this receptor is mediated by G-proteins that activate phospholipase C. Seems to act through a G(q) and G(i)-mediated pathway.<ref>PMID:12496284</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-A crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Galphaq-coupled partial agonist, compound 1 is a dual Galphaq and Galphas-coupled full agonist. compound 1 binds in the lipid-rich region of the receptor near intracellular loop 2 (ICL2), in which the stabilization of ICL2 by the ligand is likely the primary mechanism for the enhanced G protein activities. The endogenous free fatty acid (FFA), gamma-linolenic acid, can be computationally modeled in this site. Both gamma-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site.
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Structural basis for GPR40 allosteric agonism and incretin stimulation.,Ho JD, Chau B, Rodgers L, Lu F, Wilbur KL, Otto KA, Chen Y, Song M, Riley JP, Yang HC, Reynolds NA, Kahl SD, Lewis AP, Groshong C, Madsen RE, Conners K, Lineswala JP, Gheyi T, Saflor MD, Lee MR, Benach J, Baker KA, Montrose-Rafizadeh C, Genin MJ, Miller AR, Hamdouchi C Nat Commun. 2018 Apr 25;9(1):1645. doi: 10.1038/s41467-017-01240-w. PMID:29695780<ref>PMID:29695780</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5kw2" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[GPR40|GPR40]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Lysozyme]]
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[[Category: Escherichia virus T4]]
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[[Category: Baker, K A]]
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[[Category: Homo sapiens]]
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[[Category: Benach, J]]
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[[Category: Large Structures]]
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[[Category: Chau, B]]
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[[Category: Baker KA]]
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[[Category: Chen, Y]]
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[[Category: Benach J]]
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[[Category: Conners, K]]
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[[Category: Chau B]]
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[[Category: Genin, M J]]
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[[Category: Chen Y]]
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[[Category: Gheyi, T]]
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[[Category: Conners K]]
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[[Category: Groshong, C]]
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[[Category: Genin MJ]]
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[[Category: Hamdouchi, C]]
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[[Category: Gheyi T]]
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[[Category: Ho, J D]]
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[[Category: Groshong C]]
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[[Category: Kahl, S D]]
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[[Category: Hamdouchi C]]
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[[Category: Lee, M R]]
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[[Category: Ho JD]]
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[[Category: Lewis, A P]]
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[[Category: Kahl SD]]
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[[Category: Linswala, J P]]
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[[Category: Lee MR]]
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[[Category: Lu, F]]
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[[Category: Lewis AP]]
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[[Category: Madsen, R E]]
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[[Category: Linswala JP]]
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[[Category: Miller, A R]]
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[[Category: Lu F]]
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[[Category: Montrose-Rafizadeh, C]]
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[[Category: Madsen RE]]
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[[Category: Otto, K A]]
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[[Category: Miller AR]]
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[[Category: Reynolds, N A]]
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[[Category: Montrose-Rafizadeh C]]
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[[Category: Riley, J P]]
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[[Category: Otto KA]]
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[[Category: Rodgers, L]]
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[[Category: Reynolds NA]]
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[[Category: Saflor, M D]]
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[[Category: Riley JP]]
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[[Category: Song, M]]
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[[Category: Rodgers L]]
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[[Category: Wilbur, K L]]
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[[Category: Saflor MD]]
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[[Category: Yang, H C]]
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[[Category: Song M]]
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[[Category: Fatty acid binding protein-hydrolase complex]]
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[[Category: Wilbur KL]]
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[[Category: Free fatty acid receptor 1]]
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[[Category: Yang H-C]]
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[[Category: G-protein coupled receptor]]
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[[Category: Lipid-binding protein]]
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Current revision

The extra-helical binding site of GPR40 and the structural basis for allosteric agonism and incretin stimulation

PDB ID 5kw2

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