| Structural highlights
Function
HCAR3_HUMAN Receptor for 3-OH-octanoid acid mediates a negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in beta-oxidation rates. Acts as a low affinity receptor for nicotinic acid. This pharmacological effect requires nicotinic acid doses that are much higher than those provided by a normal diet.[1] [2]
Publication Abstract from PubMed
Hydroxycarboxylic acid receptor 3 (HCAR3), a class A G-protein-coupled receptor, is an important cellular energy metabolism sensor with a key role in the regulation of lipolysis in humans. HCAR3 is deeply involved in many physiological processes and serves as a valuable target for the treatment of metabolic diseases, tumors, and immune diseases. Here, we report four cryoelectron microscopy (cryo-EM) structures of human HCAR3-Gi1 complexes with or without agonists: the endogenous ligand 3-hydroxyoctanoic acid, the drug niacin, the highly subtype-specific agonist compound 5c (4-(n-propyl)amino-3-nitrobenzoic acid), and the apo form. Together with mutagenesis and functional analyses, we revealed the recognition mechanisms of HCAR3 for different agonists. In addition, the key residues that determine the ligand selectivity between HCAR2 and HCAR3 were also illuminated. Overall, these findings provide a structural basis for the ligand recognition, activation, and selectivity and G-protein coupling mechanisms of HCAR3, which contribute to the design of HCAR3-targeting drugs with high efficacy and selectivity.
Structural basis for ligand recognition of the human hydroxycarboxylic acid receptor HCAR3.,Ye F, Pan X, Zhang Z, Xiang X, Li X, Zhang B, Ning P, Liu A, Wang Q, Gong K, Li J, Zhu L, Qian C, Chen G, Du Y Cell Rep. 2024 Oct 19;43(11):114895. doi: 10.1016/j.celrep.2024.114895. PMID:39427321[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M, Ignar DM, Murdock PR, Steplewski K, Green A, Brown AJ, Dowell SJ, Szekeres PG, Hassall DG, Marshall FH, Wilson S, Pike NB. Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem. 2003 Mar 14;278(11):9869-74. PMID:12522134 doi:10.1074/jbc.M210695200
- ↑ Ahmed K, Tunaru S, Langhans CD, Hanson J, Michalski CW, Kölker S, Jones PM, Okun JG, Offermanns S. Deorphanization of GPR109B as a receptor for the beta-oxidation intermediate 3-OH-octanoic acid and its role in the regulation of lipolysis. J Biol Chem. 2009 Aug 14;284(33):21928-21933. PMID:19561068 doi:10.1074/jbc.M109.019455
- ↑ Ye F, Pan X, Zhang Z, Xiang X, Li X, Zhang B, Ning P, Liu A, Wang Q, Gong K, Li J, Zhu L, Qian C, Chen G, Du Y. Structural basis for ligand recognition of the human hydroxycarboxylic acid receptor HCAR3. Cell Rep. 2024 Oct 19;43(11):114895. PMID:39427321 doi:10.1016/j.celrep.2024.114895
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