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| | ==Crystal structure of Human GPR40 bound to allosteric agonist TAK-875== | | ==Crystal structure of Human GPR40 bound to allosteric agonist TAK-875== |
| - | <StructureSection load='4phu' size='340' side='right' caption='[[4phu]], [[Resolution|resolution]] 2.33Å' scene=''> | + | <StructureSection load='4phu' size='340' side='right'caption='[[4phu]], [[Resolution|resolution]] 2.33Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4phu]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PHU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PHU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4phu]] 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=4PHU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PHU FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=2YB:[(3S)-6-({2,6-DIMETHYL-4-[3-(METHYLSULFONYL)PROPOXY]BIPHENYL-3-YL}METHOXY)-2,3-DIHYDRO-1-BENZOFURAN-3-YL]ACETIC+ACID'>2YB</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=2YB:[(3S)-6-({2,6-DIMETHYL-4-[3-(METHYLSULFONYL)PROPOXY]BIPHENYL-3-YL}METHOXY)-2,3-DIHYDRO-1-BENZOFURAN-3-YL]ACETIC+ACID'>2YB</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FFAR1, GPR40 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4phu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4phu OCA], [https://pdbe.org/4phu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4phu RCSB], [https://www.ebi.ac.uk/pdbsum/4phu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4phu ProSAT]</span></td></tr> |
| - | <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>
| + | |
| - | <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=4phu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4phu OCA], [http://pdbe.org/4phu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4phu RCSB], [http://www.ebi.ac.uk/pdbsum/4phu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4phu ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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> | + | [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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4phu" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4phu" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[GPR40|GPR40]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Escherichia virus T4]] |
| - | [[Category: Lysozyme]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Aertgeerts, K]] | + | [[Category: Large Structures]] |
| - | [[Category: Gruswitz, F]] | + | [[Category: Aertgeerts K]] |
| - | [[Category: Hirozane, Y]] | + | [[Category: Gruswitz F]] |
| - | [[Category: Ivetac, A]] | + | [[Category: Hirozane Y]] |
| - | [[Category: Jennings, A]] | + | [[Category: Ivetac A]] |
| - | [[Category: Kefala, G]] | + | [[Category: Jennings A]] |
| - | [[Category: Lane, W]] | + | [[Category: Kefala G]] |
| - | [[Category: Nguyen, J]] | + | [[Category: Lane W]] |
| - | [[Category: Okada, K]] | + | [[Category: Nguyen J]] |
| - | [[Category: Snell, G]] | + | [[Category: Okada K]] |
| - | [[Category: Srivastava, A]] | + | [[Category: Snell G]] |
| - | [[Category: Yano, J K]] | + | [[Category: Srivastava A]] |
| - | [[Category: Class some]]
| + | [[Category: Yano JK]] |
| - | [[Category: Fasiglifam]]
| + | |
| - | [[Category: Fatty acid binding protein]]
| + | |
| - | [[Category: Fatty acid binding protein-hydrolase complex]]
| + | |
| - | [[Category: G-protein coupled receptor]]
| + | |
| - | [[Category: Gpr40]]
| + | |
| - | [[Category: Tak-875]]
| + | |
| - | [[Category: Type ii diabetes]]
| + | |
| Structural highlights
Function
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.[1] 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.[2]
Publication Abstract from PubMed
Human GPR40 receptor (hGPR40), also known as free fatty-acid receptor 1 (FFAR1), is a G-protein-coupled receptor that binds long-chain free fatty acids to enhance glucose-dependent insulin secretion. Novel treatments for type-2 diabetes mellitus are therefore possible by targeting hGPR40 with partial or full agonists. TAK-875, or fasiglifam, is an orally available, potent and selective partial agonist of hGPR40 receptor, which reached phase III clinical trials for the potential treatment of type-2 diabetes mellitus. Data from clinical studies indicate that TAK-875, which is an ago-allosteric modulator of hGPR40 (ref. 3), demonstrates improved glycaemic control and low hypoglycaemic risk in diabetic patients. Here we report the crystal structure of hGPR40 receptor bound to TAK-875 at 2.3 A resolution. The co-complex structure reveals a unique binding mode of TAK-875 and suggests that entry to the non-canonical binding pocket most probably occurs via the lipid bilayer. The atomic details of the extensive charge network in the ligand binding pocket reveal additional interactions not identified in previous studies and contribute to a clear understanding of TAK-875 binding to the receptor. The hGPR40-TAK-875 structure also provides insights into the plausible binding of multiple ligands to the receptor, which has been observed in radioligand binding and Ca2+ influx assay studies. Comparison of the transmembrane helix architecture with other G-protein-coupled receptors suggests that the crystallized TAK-875-bound hGPR40 complex is in an inactive-like state.
High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875.,Srivastava A, Yano J, Hirozane Y, Kefala G, Gruswitz F, Snell G, Lane W, Ivetac A, Aertgeerts K, Nguyen J, Jennings A, Okada K Nature. 2014 Jul 20. doi: 10.1038/nature13494. PMID:25043059[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Moussa SH, Kuznetsov V, Tran TA, Sacchettini JC, Young R. Protein determinants of phage T4 lysis inhibition. Protein Sci. 2012 Apr;21(4):571-82. doi: 10.1002/pro.2042. Epub 2012 Mar 2. PMID:22389108 doi:http://dx.doi.org/10.1002/pro.2042
- ↑ Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Ellis C, Elshourbagy NA, Goetz AS, Minnick DT, Murdock PR, Sauls HR Jr, Shabon U, Spinage LD, Strum JC, Szekeres PG, Tan KB, Way JM, Ignar DM, Wilson S, Muir AI. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem. 2003 Mar 28;278(13):11303-11. Epub 2002 Dec 19. PMID:12496284 doi:http://dx.doi.org/10.1074/jbc.M211495200
- ↑ Srivastava A, Yano J, Hirozane Y, Kefala G, Gruswitz F, Snell G, Lane W, Ivetac A, Aertgeerts K, Nguyen J, Jennings A, Okada K. High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature. 2014 Jul 20. doi: 10.1038/nature13494. PMID:25043059 doi:http://dx.doi.org/10.1038/nature13494
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