5tzr

From Proteopedia

(Difference between revisions)

Revision as of 12:23, 23 September 2020

GPR40 in complex with partial agonist MK-8666

Structural highlights

5tzr is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Related:	5tzy
Activity:	Lysozyme, with EC number 3.2.1.17
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1]

Publication Abstract from PubMed

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-A 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-A 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.

Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40.,Lu J, Byrne N, Wang J, Bricogne G, Brown FK, Chobanian HR, Colletti SL, Di Salvo J, Thomas-Fowlkes B, Guo Y, Hall DL, Hadix J, Hastings NB, Hermes JD, Ho T, Howard AD, Josien H, Kornienko M, Lumb KJ, Miller MW, Patel SB, Pio B, Plummer CW, Sherborne BS, Sheth P, Souza S, Tummala S, Vonrhein C, Webb M, Allen SJ, Johnston JM, Weinglass AB, Sharma S, Soisson SM Nat Struct Mol Biol. 2017 Jul;24(7):570-577. doi: 10.1038/nsmb.3417. Epub 2017, Jun 5. PMID:28581512^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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
↑ Lu J, Byrne N, Wang J, Bricogne G, Brown FK, Chobanian HR, Colletti SL, Di Salvo J, Thomas-Fowlkes B, Guo Y, Hall DL, Hadix J, Hastings NB, Hermes JD, Ho T, Howard AD, Josien H, Kornienko M, Lumb KJ, Miller MW, Patel SB, Pio B, Plummer CW, Sherborne BS, Sheth P, Souza S, Tummala S, Vonrhein C, Webb M, Allen SJ, Johnston JM, Weinglass AB, Sharma S, Soisson SM. Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. Nat Struct Mol Biol. 2017 Jul;24(7):570-577. doi: 10.1038/nsmb.3417. Epub 2017, Jun 5. PMID:28581512 doi:http://dx.doi.org/10.1038/nsmb.3417

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5tzr"

@@ Line 1: / Line 1: @@
 ==GPR40 in complex with partial agonist MK-8666==
-<StructureSection load='5tzr' size='340' side='right' caption='[[5tzr]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+<StructureSection load='5tzr' size='340' side='right'caption='[[5tzr]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5tzr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TZR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TZR FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5tzr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TZR OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5TZR 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=MK6:(5aR,6S,6aS)-3-({2,6-dimethyl-4-[3-(methylsulfonyl)propoxy][1,1-biphenyl]-3-yl}methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylic+acid'>MK6</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=MK6:(5aR,6S,6aS)-3-({2,6-dimethyl-4-[3-(methylsulfonyl)propoxy][1,1-biphenyl]-3-yl}methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylic+acid'>MK6</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tzy|5tzy]]</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=5tzr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tzr OCA], [http://pdbe.org/5tzr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tzr RCSB], [http://www.ebi.ac.uk/pdbsum/5tzr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tzr ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5tzr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tzr OCA], [http://pdbe.org/5tzr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tzr RCSB], [http://www.ebi.ac.uk/pdbsum/5tzr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tzr ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 24: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Lysozyme]]
 [[Category: Byrne, N]]

5tzr

From Proteopedia

Revision as of 12:23, 23 September 2020

GPR40 in complex with partial agonist MK-8666

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox