EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation.
ジャーナル・号・ページ	Mol Cell, Vol. 83, Issue 17, Page 3171-33187.e7, Year 2023
掲載日	2023年9月7日
著者	Chang Zhao / Heli Wang / Ying Liu / Lin Cheng / Bo Wang / Xiaowen Tian / Hong Fu / Chao Wu / Ziyan Li / Chenglong Shen / Jingjing Yu / Shengyong Yang / Hongbo Hu / Ping Fu / Liang Ma / Chuanxin Wang / Wei Yan / Zhenhua Shao /
PubMed 要旨	Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body β-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 ...Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body β-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates distinct pathophysiological events by activating G protein or β-arrestin effectors. Here, we characterize compound 9n as a G-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy in RAW264.7 macrophages via a specific HCAR2-G pathway. Furthermore, four structures of HCAR2-G complex bound to orthosteric agonists (niacin or monomethyl fumarate), compound 9n, and niacin together with compound 9n simultaneously reveal a common orthosteric site and a unique allosteric site. Combined with functional studies, we decipher the action framework of biased allosteric modulation of compound 9n on the orthosteric site. Moreover, co-administration of compound 9n with orthosteric agonists could enhance anti-inflammatory effects in the mouse model of colitis. Together, our study provides insight to understand the molecular pharmacology of the BAM and facilitates exploring the therapeutic potential of the BAM with orthosteric drugs.
リンク	Mol Cell / PubMed:37597514
手法	EM (単粒子)
解像度	2.78 - 3.5 Å
構造データ	36300 8jhy EMDB-36300, PDB-8jhy: Cryo-EM structure of compound 9n bound ketone body receptor HCAR2-Gi signaling complex 手法: EM (単粒子) / 解像度: 2.87 Å 36312 8jii EMDB-36312, PDB-8jii: Cryo-EM structure of compound 9n and niacin bound ketone body receptor HCAR2-Gi signaling complex 手法: EM (単粒子) / 解像度: 3.17 Å 36317 8jil EMDB-36317, PDB-8jil: Cryo-EM structure of niacin bound ketone body receptor HCAR2-Gi signaling complex 手法: EM (単粒子) / 解像度: 3.5 Å 36318 8jim EMDB-36318, PDB-8jim: Cryo-EM structure of MMF bound ketone body receptor HCAR2-Gi signaling complex 手法: EM (単粒子) / 解像度: 2.98 Å EMDB-36490: Cryo-EM map of human receptor R2 手法: EM (単粒子) / 解像度: 3.21 Å EMDB-36491: Cryo-EM map of human Gi heterotrimer 手法: EM (単粒子) / 解像度: 2.78 Å EMDB-36492: Cryo-EM map of human receptor R2 手法: EM (単粒子) / 解像度: 3.37 Å EMDB-36493: Cryo-EM map of human Gi heterotrimer 手法: EM (単粒子) / 解像度: 3.12 Å EMDB-36494: Cryo-EM map of human receptor R2 手法: EM (単粒子) / 解像度: 3.24 Å EMDB-36495: Cryo-EM map of human Gi heterotrimer 手法: EM (単粒子) / 解像度: 2.95 Å EMDB-36496: Cryo-EM map of human receptor R2 手法: EM (単粒子) / 解像度: 3.37 Å EMDB-36497: Cryo-EM map of human Gi heterotrimer 手法: EM (単粒子) / 解像度: 2.96 Å EMDB-36505: Cryo-EM map of human receptor R2 in complex with Gi protein 手法: EM (単粒子) / 解像度: 2.87 Å EMDB-36506: Cryo-EM map of human receptor R2 in complex with Gi protein 手法: EM (単粒子) / 解像度: 3.17 Å EMDB-36507: Cryo-EM map of human receptor R2 in complex with Gi protein 手法: EM (単粒子) / 解像度: 3.05 Å EMDB-36508: Cryo-EM map of human receptor R2 in complex with Gi protein 手法: EM (単粒子) / 解像度: 2.98 Å
化合物	ChemComp-IX8: 7-methyl-N-[(2R)-1-phenoxypropan-2-yl]-3-(4-propan-2-ylphenyl)pyrazolo[1,5-a]pyrimidine-6-carboxamide ChemComp-CLR: CHOLESTEROL / コレステロ-ル / コレステロール ChemComp-NIO: NICOTINIC ACID / ニコチン酸 / ニコチン酸 ChemComp-HOH: WATER / 水 ChemComp-AW9: (2Z)-4-methoxy-4-oxobut-2-enoic acid
由来	homo sapiens (ヒト) mus musculus (ハツカネズミ)
キーワード	MEMBRANE PROTEIN (膜タンパク質) / Complex / Agonist (アゴニスト)