8ijb

From Proteopedia

Cryo-EM structure of human HCAR2-Gi complex with acipimox

PDB ID 8ijb

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Structural highlights

8ijb is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.23Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1]

Publication Abstract from PubMed

Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply involved in many pathophysiological processes and serves as an attractive target for the treatment of cardiovascular, neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases. Here, we report four cryo-EM structures of human HCAR2-Gi1 complexes with or without agonists, including the drugs niacin (2.69 A) and acipimox (3.23 A), the highly subtype-specific agonist MK-6892 (3.25 A), and apo form (3.28 A). Combined with molecular dynamics simulation and functional analysis, we have revealed the recognition mechanism of HCAR2 for different agonists and summarized the general pharmacophore features of HCAR2 agonists, which are based on three key residues R111(3.36), S179(45.52), and Y284(7.43). Notably, the MK-6892-HCAR2 structure shows an extended binding pocket relative to other agonist-bound HCAR2 complexes. In addition, the key residues that determine the ligand selectivity between the HCAR2 and HCAR3 are also illuminated. Our findings provide structural insights into the ligand recognition, selectivity, activation, and G protein coupling mechanism of HCAR2, which shed light on the design of new HCAR2-targeting drugs for greater efficacy, higher selectivity, and fewer or no side effects.

Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2.,Pan X, Ye F, Ning P, Zhang Z, Li X, Zhang B, Wang Q, Chen G, Gao W, Qiu C, Wu Z, Li J, Zhu L, Xia J, Gong K, Du Y Cell Discov. 2023 Nov 28;9(1):118. doi: 10.1038/s41421-023-00610-7. PMID:38012147^[2]

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

References

↑ Kostylina G, Simon D, Fey MF, Yousefi S, Simon HU. Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A). Cell Death Differ. 2008 Jan;15(1):134-42. PMID:17932499 doi:10.1038/sj.cdd.4402238
↑ Pan X, Ye F, Ning P, Zhang Z, Li X, Zhang B, Wang Q, Chen G, Gao W, Qiu C, Wu Z, Li J, Zhu L, Xia J, Gong K, Du Y. Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2. Cell Discov. 2023 Nov 28;9(1):118. PMID:38012147 doi:10.1038/s41421-023-00610-7