8j6j
From Proteopedia
Cryo-EM structure of thehydroxycarboxylic acid receptor 2-Gi protein complex bound with GSK256073
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedNiacin, an age-old lipid-lowering drug, acts through the hydroxycarboxylic acid receptor 2 (HCAR2), a G-protein-coupled receptor (GPCR). Yet, its use is hindered by side effects like skin flushing. To address this, specific HCAR2 agonists, like MK-6892 and GSK256073, with fewer adverse effects have been created. However, the activation mechanism of HCAR2 by niacin and these new agonists is not well understood. Here, we present three cryoelectron microscopy structures of Gi-coupled HCAR2 bound to niacin, MK-6892, and GSK256073. Our findings show that different ligands induce varying binding pockets in HCAR2, influenced by aromatic amino acid clusters (W91(ECL1), H161(4.59), W188(5.38), H189(5.39), and F193(5.43)) from receptors ECL1, TM4, and TM5. Additionally, conserved residues R111(3.36) and Y284(7.43), unique to the HCA receptor family, likely initiate activation signal propagation in HCAR2. This study provides insights into ligand recognition, receptor activation, and G protein coupling mediated by HCAR2, laying the groundwork for developing HCAR2-targeted drugs. Molecular recognition of niacin and lipid-lowering drugs by the human hydroxycarboxylic acid receptor 2.,Zhu S, Yuan Q, Li X, He X, Shen S, Wang D, Li J, Cheng X, Duan X, Xu HE, Duan J Cell Rep. 2023 Nov 28;42(11):113406. doi: 10.1016/j.celrep.2023.113406. Epub 2023 , Nov 11. PMID:37952153[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Duan J | Duan X | Xu HE | Yuan Q | Zhu S
