登録情報 データベース : EMDB / ID : EMD-38039 ダウンロードとリンクタイトル Cryo-EM structure of CB2-G protein complex マップデータ 詳細 試料複合体 : YL025-bound CB2R in complex with Gi heterotrimer複合体 : CB2R-Giタンパク質・ペプチド : Guanine nucleotide-binding protein G(i) subunit alpha-1タンパク質・ペプチド : Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1タンパク質・ペプチド : Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2タンパク質・ペプチド : Cannabinoid receptor 2複合体 : scFV16リガンド : 4-[3-(4-fluoranyl-2~{H}-indazol-7-yl)-1,2,4-oxadiazol-5-yl]-1-(4-fluorophenyl)azepan-2-one 詳細 キーワード GPCR / CB2 / Gi1 / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex機能・相同性 機能・相同性情報分子機能 ドメイン・相同性 構成要素
trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / cannabinoid receptor activity / negative regulation of mast cell activation / negative regulation of synaptic transmission, GABAergic / negative regulation of action potential / Class A/1 (Rhodopsin-like receptors) / leukocyte chemotaxis / extrinsic component of cytoplasmic side of plasma membrane / regulation of metabolic process / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger ... trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / cannabinoid receptor activity / negative regulation of mast cell activation / negative regulation of synaptic transmission, GABAergic / negative regulation of action potential / Class A/1 (Rhodopsin-like receptors) / leukocyte chemotaxis / extrinsic component of cytoplasmic side of plasma membrane / regulation of metabolic process / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to forskolin / response to amphetamine / regulation of mitotic spindle organization / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / response to peptide hormone / G-protein beta/gamma-subunit complex binding / centriolar satellite / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / G protein activity / GTPase binding / Ca2+ pathway / retina development in camera-type eye / midbody / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / 加水分解酵素; 酸無水物に作用; GTPに作用・細胞または細胞小器官の運動に関与 / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / perikaryon / response to lipopolysaccharide / postsynaptic membrane / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / ciliary basal body / immune response / G protein-coupled receptor signaling pathway / inflammatory response / lysosomal membrane / cell division / GTPase activity / synapse / centrosome / dendrite / protein-containing complex binding / GTP binding 類似検索 - 分子機能 Cannabinoid receptor type 2 / Cannabinoid receptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit ... Cannabinoid receptor type 2 / Cannabinoid receptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase 類似検索 - ドメイン・相同性 Cannabinoid receptor 2 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1 類似検索 - 構成要素生物種 Homo sapiens (ヒト) / Mus musculus (ハツカネズミ)手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 3.13 Å 詳細 データ登録者Shen SY / Yang ZQ / Shao ZH 資金援助 中国, 1件 詳細 詳細を隠すOrganization Grant number 国 National Natural Science Foundation of China (NSFC) 31972916 中国
引用ジャーナル : Proc Natl Acad Sci U S A / 年 : 2024タイトル : Entropy drives the ligand recognition in G-protein-coupled receptor subtypes.著者: Xin Yang / Pei Zhou / Siyuan Shen / Qian Hu / Chenyu Tian / Anjie Xia / Yifei Wang / Zhiqian Yang / Jinshan Nan / Yangli Zhou / Shasha Chen / Xiaowen Tian / Chao Wu / Guifeng Lin / Liting ... 著者 : Xin Yang / Pei Zhou / Siyuan Shen / Qian Hu / Chenyu Tian / Anjie Xia / Yifei Wang / Zhiqian Yang / Jinshan Nan / Yangli Zhou / Shasha Chen / Xiaowen Tian / Chao Wu / Guifeng Lin / Liting Zhang / Kexin Wang / Tao Zheng / Jun Zou / Wei Yan / Zhenhua Shao / Shengyong Yang / 要旨 : Achieving ligand subtype selectivity within highly homologous subtypes of G-protein-coupled receptor (GPCR) is critical yet challenging for GPCR drug discovery, primarily due to the unclear mechanism ... Achieving ligand subtype selectivity within highly homologous subtypes of G-protein-coupled receptor (GPCR) is critical yet challenging for GPCR drug discovery, primarily due to the unclear mechanism underlying ligand subtype selectivity, which hampers the rational design of subtype-selective ligands. Herein, we disclose an unusual molecular mechanism of entropy-driven ligand recognition in cannabinoid (CB) receptor subtypes, revealed through atomic-level molecular dynamics simulations, cryoelectron microscopy structure, and mutagenesis experiments. This mechanism is attributed to the distinct conformational dynamics of the receptor's orthosteric pocket, leading to variations in ligand binding entropy and consequently, differential binding affinities, which culminate in specific ligand recognition. We experimentally validated this mechanism and leveraged it to design ligands with enhanced or ablated subtype selectivity. One such ligand demonstrated favorable pharmacokinetic properties and significant efficacy in rodent inflammatory analgesic models. More importantly, it is precisely due to the high subtype selectivity obtained based on this mechanism that this ligand does not show addictive properties in animal models. Our findings elucidate the unconventional role of entropy in CB receptor subtype selectivity and suggest a strategy for rational design of ligands to achieve entropy-driven subtype selectivity for many pharmaceutically important GPCRs. 履歴 登録 2023年11月14日 - ヘッダ(付随情報) 公開 2024年11月20日 - マップ公開 2024年11月20日 - 更新 2025年2月12日 - 現状 2025年2月12日 処理サイト : PDBj / 状態 : 公開
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