8iyh: Difference between revisions
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The | ==Structure of MK6892-GPR109A-G-protein complex== | ||
<StructureSection load='8iyh' size='340' side='right'caption='[[8iyh]], [[Resolution|resolution]] 3.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8iyh]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8IYH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8IYH FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FI7:2-[[2,2-dimethyl-3-[3-(5-oxidanylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]propanoyl]amino]cyclohexene-1-carboxylic+acid'>FI7</scene></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=8iyh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8iyh OCA], [https://pdbe.org/8iyh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8iyh RCSB], [https://www.ebi.ac.uk/pdbsum/8iyh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8iyh ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin receptor or GPR109A, is a prototypical GPCR that plays a central role in the inhibition of lipolytic and atherogenic activities. Its activation also results in vasodilation that is linked to the side-effect of flushing associated with dyslipidemia drugs such as niacin. GPR109A continues to be a target for developing potential therapeutics in dyslipidemia with minimized flushing response. Here, we present cryo-EM structures of the GPR109A in complex with dyslipidemia drugs, niacin or acipimox, non-flushing agonists, MK6892 or GSK256073, and recently approved psoriasis drug, monomethyl fumarate (MMF). These structures elucidate the binding mechanism of agonists, molecular basis of receptor activation, and insights into biased signaling elicited by some of the agonists. The structural framework also allows us to engineer receptor mutants that exhibit G-protein signaling bias, and therefore, our study may help in structure-guided drug discovery efforts targeting this receptor. | |||
Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution.,Yadav MK, Sarma P, Maharana J, Ganguly M, Mishra S, Zaidi N, Dalal A, Singh V, Saha S, Mahajan G, Sharma S, Chami M, Banerjee R, Shukla AK Nat Commun. 2024 Mar 2;15(1):1939. doi: 10.1038/s41467-024-46239-2. PMID:38431681<ref>PMID:38431681</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8iyh" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: Sarma | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Banerjee R]] | |||
[[Category: Chami M]] | |||
[[Category: Sarma P]] | |||
[[Category: Shukla AK]] | |||
[[Category: Yadav MK]] | |||
Latest revision as of 12:55, 9 October 2024
Structure of MK6892-GPR109A-G-protein complexStructure of MK6892-GPR109A-G-protein complex
Structural highlights
Publication Abstract from PubMedThe Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin receptor or GPR109A, is a prototypical GPCR that plays a central role in the inhibition of lipolytic and atherogenic activities. Its activation also results in vasodilation that is linked to the side-effect of flushing associated with dyslipidemia drugs such as niacin. GPR109A continues to be a target for developing potential therapeutics in dyslipidemia with minimized flushing response. Here, we present cryo-EM structures of the GPR109A in complex with dyslipidemia drugs, niacin or acipimox, non-flushing agonists, MK6892 or GSK256073, and recently approved psoriasis drug, monomethyl fumarate (MMF). These structures elucidate the binding mechanism of agonists, molecular basis of receptor activation, and insights into biased signaling elicited by some of the agonists. The structural framework also allows us to engineer receptor mutants that exhibit G-protein signaling bias, and therefore, our study may help in structure-guided drug discovery efforts targeting this receptor. Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution.,Yadav MK, Sarma P, Maharana J, Ganguly M, Mishra S, Zaidi N, Dalal A, Singh V, Saha S, Mahajan G, Sharma S, Chami M, Banerjee R, Shukla AK Nat Commun. 2024 Mar 2;15(1):1939. doi: 10.1038/s41467-024-46239-2. PMID:38431681[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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