View source for 9kt7


==Cryo-EM structure of HCA2-Gi complex with MK6892==
<StructureSection load='9kt7' size='340' side='right'caption='[[9kt7]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9kt7]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9KT7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9KT7 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]] 2.8&#8491;</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=9kt7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9kt7 OCA], [https://pdbe.org/9kt7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9kt7 RCSB], [https://www.ebi.ac.uk/pdbsum/9kt7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9kt7 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/HCAR2_HUMAN HCAR2_HUMAN] Acts as a high affinity receptor for both nicotinic acid (also known as niacin) and (D)-beta-hydroxybutyrate and mediates increased adiponectin secretion and decreased lipolysis through G(i)-protein-mediated inhibition of adenylyl cyclase. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet. Mediates nicotinic acid-induced apoptosis in mature neutrophils. Receptor activation by nicotinic acid results in reduced cAMP levels which may affect activity of cAMP-dependent protein kinase A and phosphorylation of target proteins, leading to neutrophil apoptosis. The rank order of potency for the displacement of nicotinic acid binding is 5-methyl pyrazole-3-carboxylic acid = pyridine-3-acetic acid > acifran > 5-methyl nicotinic acid = acipimox >> nicotinuric acid = nicotinamide.<ref>PMID:17932499</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Hydroxy-carboxylic acid receptors HCA1, HCA2, and HCA3 can be activated by important intermediates of energy metabolism. Despite the research focusing on HCA2, its clinical application has been limited by adverse effects. Therefore, the role of HCA1 as a promising target for the treatment of lipolysis warrants further exploration. As HCAs exhibit high similarity when activated with diverse selective agonists, a conserved yet unique activation mechanism for HCAs remains undisclosed. Herein, we unveil the cryo-electron microscopy structures of the 3,5-DHBA-HCA1-Gi signaling complex, the acifran- and MK6892-bound HCA2-Gi signaling complexes, and the acifran-HCA3-Gi signaling complex. Comparative analysis across HCAs reveals key residues in HCA1 contributing to the stabilization of the ligand-binding pocket. Furthermore, chimeric complexes and mutational analyses identify residues that are pivotal for HCA2 and HCA3 selectivity. Our findings elucidate critical structural insights into the mechanisms of ligand recognition and activation within HCA1 and broaden our comprehension of ligand specificity binding across the HCA family.

Insights into the Activation Mechanism of HCA1, HCA2, and HCA3.,Wang J, Qian Y, Han Z, Wang Y, Liu Y, Li J, Duanmu Q, Ye S, Qiao A, Wu S J Med Chem. 2025 Feb 27;68(4):4527-4539. doi: 10.1021/acs.jmedchem.4c02567. Epub , 2025 Feb 12. PMID:39936872<ref>PMID:39936872</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9kt7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Wu S]]