8J6P

Cryo-EM structure of the MK-6892-bound human HCAR2-Gi1 complex

8J6P の概要

• エントリーDOI: 10.2210/pdb8j6p/pdb
• EMDBエントリー: 36010
• 分子名称: 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, ... (10 entities in total)
• 機能のキーワード: hydroxycarboxylic acid receptor, niacin, compound 9n, class a gpcr, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 146409.71

構造登録者

Mao, C.,Gao, M.,Zang, S.,Zhu, Y.,Ma, X.,Zhang, Y. (登録日: 2023-04-26, 公開日: 2023-12-06, 最終更新日: 2025-07-23)

主引用文献

Mao, C.,Gao, M.,Zang, S.K.,Zhu, Y.,Shen, D.D.,Chen, L.N.,Yang, L.,Wang, Z.,Zhang, H.,Wang, W.W.,Shen, Q.,Lu, Y.,Ma, X.,Zhang, Y.
Orthosteric and allosteric modulation of human HCAR2 signaling complex.
Nat Commun, 14:7620-7620, 2023

PubMed Abstract: Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors (HCARs). HCAR2 is one such receptor, activated by endogenous β-hydroxybutyrate (3-HB) and butyrate, and is the target for Niacin. Interest in HCAR2 has been driven by its potential as a therapeutic target in cardiovascular and neuroinflammatory diseases. However, the limited understanding of how ligands bind to this receptor has hindered the development of alternative drugs able to avoid the common flushing side-effects associated with Niacin therapy. Here, we present three high-resolution structures of HCAR2-Gi1 complexes bound to four different ligands, one potent synthetic agonist (MK-6892) bound alone, and the two structures bound to the allosteric agonist compound 9n in conjunction with either the endogenous ligand 3-HB or niacin. These structures coupled with our functional and computational analyses further our understanding of ligand recognition, allosteric modulation, and activation of HCAR2 and pave the way for the development of high-efficiency drugs with reduced side-effects.

PubMed: 37993467
DOI: 10.1038/s41467-023-43537-z

実験手法

ELECTRON MICROSCOPY (2.55 Å)