+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8fx5 | ||||||||||||||||||||||||
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タイトル | Human M4 muscarinic acetylcholine receptor complex with Gi1 and xanomeline | ||||||||||||||||||||||||
要素 |
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キーワード | MEMBRANE PROTEIN/SIGNALING PROTEIN / 7 transmembrane receptor / SIGNALING PROTEIN-IMMUNE SYSTEM complex / MEMBRANE PROTEIN / MEMBRANE PROTEIN-SIGNALING PROTEIN-IMMUNE SYSTEM complex / MEMBRANE PROTEIN-SIGNALING PROTEIN complex | ||||||||||||||||||||||||
機能・相同性 | 機能・相同性情報 Adenylate cyclase inhibitory pathway / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / Muscarinic acetylcholine receptors / Extra-nuclear estrogen signaling / G protein-coupled acetylcholine receptor activity / G alpha (i) signalling events / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / G protein-coupled serotonin receptor activity / GTPase activating protein binding ...Adenylate cyclase inhibitory pathway / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / Muscarinic acetylcholine receptors / Extra-nuclear estrogen signaling / G protein-coupled acetylcholine receptor activity / G alpha (i) signalling events / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / G protein-coupled serotonin receptor activity / GTPase activating protein binding / negative regulation of synaptic transmission / regulation of locomotion / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / D2 dopamine receptor binding / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / G-protein beta/gamma-subunit complex binding / G protein-coupled receptor binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / 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 / G beta:gamma signalling through CDC42 / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GDP binding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / 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 / cell cortex / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / midbody / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / chemical synaptic transmission / postsynaptic membrane / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / lysosomal membrane / cell division / GTPase activity / centrosome / dendrite / synapse / GTP binding / protein-containing complex binding / nucleolus / magnesium ion binding / signal transduction / protein-containing complex / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm 類似検索 - 分子機能 | ||||||||||||||||||||||||
生物種 | Homo sapiens (ヒト) Mus musculus (ハツカネズミ) | ||||||||||||||||||||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.45 Å | ||||||||||||||||||||||||
データ登録者 | Vuckovic, Z. / Mobbs, J.I. / Glukhova, A. / Sexton, P.M. / Danev, R. / Thal, D.M. | ||||||||||||||||||||||||
資金援助 | 英国, オーストラリア, 日本, 7件
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引用 | ジャーナル: Nat Commun / 年: 2023 タイトル: Xanomeline displays concomitant orthosteric and allosteric binding modes at the M mAChR. 著者: Wessel A C Burger / Vi Pham / Ziva Vuckovic / Alexander S Powers / Jesse I Mobbs / Yianni Laloudakis / Alisa Glukhova / Denise Wootten / Andrew B Tobin / Patrick M Sexton / Steven M Paul / ...著者: Wessel A C Burger / Vi Pham / Ziva Vuckovic / Alexander S Powers / Jesse I Mobbs / Yianni Laloudakis / Alisa Glukhova / Denise Wootten / Andrew B Tobin / Patrick M Sexton / Steven M Paul / Christian C Felder / Radostin Danev / Ron O Dror / Arthur Christopoulos / Celine Valant / David M Thal / 要旨: The M muscarinic acetylcholine receptor (M mAChR) has emerged as a drug target of high therapeutic interest due to its expression in regions of the brain involved in the regulation of psychosis, ...The M muscarinic acetylcholine receptor (M mAChR) has emerged as a drug target of high therapeutic interest due to its expression in regions of the brain involved in the regulation of psychosis, cognition, and addiction. The mAChR agonist, xanomeline, has provided significant improvement in the Positive and Negative Symptom Scale (PANSS) scores in a Phase II clinical trial for the treatment of patients suffering from schizophrenia. Here we report the active state cryo-EM structure of xanomeline bound to the human M mAChR in complex with the heterotrimeric G transducer protein. Unexpectedly, two molecules of xanomeline were found to concomitantly bind to the monomeric M mAChR, with one molecule bound in the orthosteric (acetylcholine-binding) site and a second molecule in an extracellular vestibular allosteric site. Molecular dynamic simulations supports the structural findings, and pharmacological validation confirmed that xanomeline acts as a dual orthosteric and allosteric ligand at the human M mAChR. These findings provide a basis for further understanding xanomeline's complex pharmacology and highlight the myriad of ways through which clinically relevant ligands can bind to and regulate GPCRs. | ||||||||||||||||||||||||
履歴 |
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-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
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-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 8fx5.cif.gz | 237.9 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8fx5.ent.gz | 182.5 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8fx5.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 8fx5_validation.pdf.gz | 1.3 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 8fx5_full_validation.pdf.gz | 1.3 MB | 表示 | |
XML形式データ | 8fx5_validation.xml.gz | 42.6 KB | 表示 | |
CIF形式データ | 8fx5_validation.cif.gz | 66 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/fx/8fx5 ftp://data.pdbj.org/pub/pdb/validation_reports/fx/8fx5 | HTTPS FTP |
-関連構造データ
関連構造データ | 29524MC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-リンク
-集合体
登録構造単位 |
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1 |
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-要素
-Guanine nucleotide-binding protein ... , 3種, 3分子 BGA
#2: タンパク質 | 分子量: 38402.867 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNB1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P62873 |
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#3: タンパク質 | 分子量: 7729.947 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: GNG2 / 発現宿主: Trichoplusia ni (イラクサキンウワバ) / 参照: UniProt: P59768 |
#5: タンパク質 | 分子量: 40414.047 Da / 分子数: 1 / Mutation: S47N, G203A, E245A, A326S / 由来タイプ: 組換発現 / 由来: (組換発現) Mus musculus (ハツカネズミ) / 遺伝子: Gnai1, Gnai-1 / 発現宿主: Trichoplusia ni (イラクサキンウワバ) / 参照: UniProt: B2RSH2 |
-タンパク質 / 抗体 , 2種, 2分子 RH
#1: タンパク質 | 分子量: 39598.277 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: CHRM4 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P08173 |
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#4: 抗体 | 分子量: 26466.486 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Trichoplusia ni (イラクサキンウワバ) |
-非ポリマー , 2種, 49分子
#6: 化合物 | #7: 水 | ChemComp-HOH / | |
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-詳細
研究の焦点であるリガンドがあるか | Y |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
-試料調製
構成要素 | 名称: M4 mAChR bound to agonist xanomeline in complex with dominant negative Galpha-i1, Gbeta1, Ggamma2, and scFv16 タイプ: COMPLEX / Entity ID: #1-#5 / 由来: MULTIPLE SOURCES |
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緩衝液 | pH: 7.5 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
-電子顕微鏡撮影
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: TFS KRIOS |
電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1500 nm / 最小 デフォーカス(公称値): 500 nm |
撮影 | 電子線照射量: 52.4 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
-解析
ソフトウェア | 名称: PHENIX / バージョン: 1.20.1_4487: / 分類: 精密化 | ||||||||||||||||||||||||
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3次元再構成 | 解像度: 2.45 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 395419 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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