登録情報 データベース : EMDB / ID : EMD-60427 ダウンロードとリンクタイトル Cryo-EM structure of the RO5263397-bound mTAAR1-Gs complex マップデータ 詳細 試料複合体 : The LSD-bound hTAAR1-Gs complexタンパク質・ペプチド : Guanine nucleotide-binding protein G(s) subunit alpha isoforms short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 : Nb35タンパク質・ペプチド : Soluble cytochrome b562,Trace amine-associated receptor 1リガンド : (4~{S})-4-(3-fluoranyl-2-methyl-phenyl)-1,3-oxazolidin-2-amine 詳細 キーワード GPCR / TAAR1 / Cryo-EM / MEMBRANE PROTEIN/IMMUNE SYSTEM / 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
G protein-coupled amine receptor activity / Amine ligand-binding receptors / trace-amine receptor activity / G alpha (s) signalling events / positive regulation of cAMP-mediated signaling / electron transport chain / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors ... G protein-coupled amine receptor activity / Amine ligand-binding receptors / trace-amine receptor activity / G alpha (s) signalling events / positive regulation of cAMP-mediated signaling / electron transport chain / 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 / 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 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / periplasmic space / electron transfer activity / iron ion binding / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / heme binding / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytoplasm / cytosol 類似検索 - 分子機能 Trace amine associated receptor 1 / Trace amine associated receptor family / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain ... Trace amine associated receptor 1 / Trace amine associated receptor family / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily 類似検索 - ドメイン・相同性 Soluble cytochrome b562 / 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 / Trace amine-associated receptor 1 類似検索 - 構成要素生物種 Homo sapiens (ヒト) / Lama glama (ラマ) / 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 : 2.96 Å 詳細 データ登録者Jiang KX / Zheng Y / Xu F 資金援助 中国, 2件 詳細 詳細を隠すOrganization Grant number 国 National Natural Science Foundation of China (NSFC) 32071194 中国 National Natural Science Foundation of China (NSFC) 32122024 中国
引用ジャーナル : Cell Rep / 年 : 2024タイトル : The versatile binding landscape of the TAAR1 pocket for LSD and other antipsychotic drug molecules.著者 : Kexin Jiang / You Zheng / Liting Zeng / Ling Wang / Fei Li / Jun Pu / Yingli Lu / Suwen Zhao / Fei Xu / 要旨 : Increasing global concerns about psychoactive substance addiction and psychotic disorders highlight the need for comprehensive research into the structure-function relationship governing ligand ... Increasing global concerns about psychoactive substance addiction and psychotic disorders highlight the need for comprehensive research into the structure-function relationship governing ligand recognition between these substances and their receptors in the brain. Recent studies indicate the significant involvement of trace amine-associated receptor 1 (TAAR1) in the signaling regulation of the hallucinogen lysergic acid diethylamide (LSD) and other antipsychotic drugs. This study presents structures of the TAAR1-Gs protein complex recognizing LSD, which exhibits a polypharmacological profile, and the partial agonist RO5263397, which is a drug candidate for schizophrenia and addiction. Moreover, we elucidate the cross-species recognition and partial activation mechanism for TAAR1, which holds promising implications from a drug discovery perspective. Through mutagenesis, functional studies, and molecular dynamics (MD) simulations, we provide a comprehensive understanding of a versatile TAAR1 pocket in recognizing various ligands as well as in the ligand-free state, underpinning the structural basis of its high adaptability. These findings offer valuable insights for the design of antipsychotic drugs. 履歴 登録 2024年6月5日 - ヘッダ(付随情報) 公開 2024年7月24日 - マップ公開 2024年7月24日 - 更新 2024年7月24日 - 現状 2024年7月24日 処理サイト : PDBc / 状態 : 公開
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