8K5C

Cryo-EM structure of Acipimox bound human hydroxy-carboxylic acid receptor 2 (Local refinement)

8K5C の概要

• エントリーDOI: 10.2210/pdb8k5c/pdb
• EMDBエントリー: 36901
• 分子名称: Human hydroxycarboxylic acid receptor 2, 5-methyl-4-oxidanyl-pyrazin-4-ium-2-carboxylic acid (2 entities in total)
• 機能のキーワード: gpcr, g-protein, membrane protein, acipimox, signaling
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 54475.43

構造登録者

Park, J.H.,Ishimoto, N.,Park, S.Y. (登録日: 2023-07-21, 公開日: 2023-11-22, 最終更新日: 2024-11-13)

主引用文献

Park, J.H.,Kawakami, K.,Ishimoto, N.,Ikuta, T.,Ohki, M.,Ekimoto, T.,Ikeguchi, M.,Lee, D.S.,Lee, Y.H.,Tame, J.R.H.,Inoue, A.,Park, S.Y.
Structural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2.
Nat Commun, 14:7150-7150, 2023

PubMed Abstract: Hydroxycarboxylic acid receptors (HCAR1, HCAR2, and HCAR3) transduce G signaling upon biding to molecules such as lactic acid, butyric acid and 3-hydroxyoctanoic acid, which are associated with lipolytic and atherogenic activity, and neuroinflammation. Although many reports have elucidated the function of HCAR2 and its potential as a therapeutic target for treating not only dyslipidemia but also neuroimmune disorders such as multiple sclerosis and Parkinson's disease, the structural basis of ligand recognition and ligand-induced G-coupling remains unclear. Here we report three cryo-EM structures of the human HCAR2-G signaling complex, each bound with different ligands: niacin, acipimox or GSK256073. All three agonists are held in a deep pocket lined by residues that are not conserved in HCAR1 and HCAR3. A distinct hairpin loop at the HCAR2 N-terminus and extra-cellular loop 2 (ECL2) completely enclose the ligand. These structures also reveal the agonist-induced conformational changes propagated to the G-protein-coupling interface during activation. Collectively, the structures presented here are expected to help in the design of ligands specific for HCAR2, leading to new drugs for the treatment of various diseases such as dyslipidemia and inflammation.

PubMed: 37932263
DOI: 10.1038/s41467-023-42764-8

実験手法

ELECTRON MICROSCOPY (3.13 Å)