8J6L

Cryo-EM structure of thehydroxycarboxylic acid receptor 2-Gi protein complex bound niacin

Summary for 8J6L

• Entry DOI: 10.2210/pdb8j6l/pdb
• EMDB information: 36007
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: hydroxycarboxylic acid receptor 2, gpcr, niacin, mk-6892, gsk256073, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 170747.85

Authors

Yuan, Q.,Zhu, S.,Duan, J.,Xu, H.E.,Duan, X. (deposition date: 2023-04-26, release date: 2024-04-03)

Primary citation

Zhu, S.,Yuan, Q.,Li, X.,He, X.,Shen, S.,Wang, D.,Li, J.,Cheng, X.,Duan, X.,Xu, H.E.,Duan, J.
Molecular recognition of niacin and lipid-lowering drugs by the human hydroxycarboxylic acid receptor 2.
Cell Rep, 42:113406-113406, 2023

PubMed Abstract: Niacin, 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, H161, W188, H189, and F193) from receptors ECL1, TM4, and TM5. Additionally, conserved residues R111 and Y284, 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.

PubMed: 37952153
DOI: 10.1016/j.celrep.2023.113406

Experimental method

ELECTRON MICROSCOPY (3.05 Å)