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基本情報
登録情報 | ![]() | ||||||||||||||||||||||||
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タイトル | Human M4 muscarinic acetylcholine receptor complex with Gi1 and xanomeline | ||||||||||||||||||||||||
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![]() | 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 | ![]() Adenylate cyclase inhibitory pathway / adenylate cyclase inhibitor activity / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / Muscarinic acetylcholine receptors / G protein-coupled acetylcholine receptor activity / Extra-nuclear estrogen signaling / G alpha (i) signalling events / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / regulation of locomotion ...Adenylate cyclase inhibitory pathway / adenylate cyclase inhibitor activity / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / Muscarinic acetylcholine receptors / G protein-coupled acetylcholine receptor activity / Extra-nuclear estrogen signaling / G alpha (i) signalling events / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / regulation of locomotion / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / negative regulation of insulin secretion / positive regulation of protein localization to cell cortex / T cell migration / D2 dopamine receptor binding / response to prostaglandin E / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to forskolin / regulation of mitotic spindle organization / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / 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 / chemical synaptic transmission / G alpha (q) signalling events / postsynaptic membrane / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / cell surface receptor signaling pathway / ciliary basal body / G protein-coupled receptor signaling pathway / lysosomal membrane / cell division / GTPase activity / synapse / centrosome / dendrite / protein-containing complex binding / GTP binding / nucleolus / magnesium ion binding / Golgi apparatus / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane 類似検索 - 分子機能 | ||||||||||||||||||||||||
生物種 | ![]() ![]() ![]() | ||||||||||||||||||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.45 Å | ||||||||||||||||||||||||
![]() | Vuckovic Z / Mobbs JI / Glukhova A / Sexton PM / Danev R / Thal DM | ||||||||||||||||||||||||
資金援助 | ![]() ![]() ![]()
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![]() | ![]() 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. | ||||||||||||||||||||||||
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マップデータ | ![]() | 51.4 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 24.3 KB 24.3 KB | 表示 表示 | ![]() |
FSC (解像度算出) | ![]() | 9.2 KB | 表示 | ![]() |
画像 | ![]() | 127.1 KB | ||
マスクデータ | ![]() | 67 MB | ![]() | |
Filedesc metadata | ![]() | 7.4 KB | ||
その他 | ![]() ![]() | 51.9 MB 52 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 8fx5MC M: このマップから作成された原子モデル C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
EMDBのページ | ![]() ![]() |
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「今月の分子」の関連する項目 |
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マップ
ファイル | ![]() | ||||||||||||||||||||||||||||||||||||
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投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 0.83 Å | ||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-マスク #1
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_29524_half_map_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #2
ファイル | emd_29524_half_map_2.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
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試料の構成要素
-全体 : M4 mAChR bound to agonist xanomeline in complex with dominant neg...
全体 | 名称: M4 mAChR bound to agonist xanomeline in complex with dominant negative Galpha-i1, Gbeta1, Ggamma2, and scFv16 |
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要素 |
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-超分子 #1: M4 mAChR bound to agonist xanomeline in complex with dominant neg...
超分子 | 名称: M4 mAChR bound to agonist xanomeline in complex with dominant negative Galpha-i1, Gbeta1, Ggamma2, and scFv16 タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#5 |
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-分子 #1: Muscarinic acetylcholine receptor M4
分子 | 名称: Muscarinic acetylcholine receptor M4 / タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 39.598277 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: DYKDDDDAMA NFTPVNGSSG NQSVRLVTSS SHNRYETVEM VFIATVTGSL SLVTVVGNIL VMLSIKVNRQ LQTVNNYFLF SLACADLII GAFSMNLYTV YIIKGYWPLG AVVCDLWLAL DYVVSNASVM NLLIISFDRY FCVTKPLTYP ARRTTKMAGL M IAAAWVLS ...文字列: DYKDDDDAMA NFTPVNGSSG NQSVRLVTSS SHNRYETVEM VFIATVTGSL SLVTVVGNIL VMLSIKVNRQ LQTVNNYFLF SLACADLII GAFSMNLYTV YIIKGYWPLG AVVCDLWLAL DYVVSNASVM NLLIISFDRY FCVTKPLTYP ARRTTKMAGL M IAAAWVLS FVLWAPAILF WQFVVGKRTV PDNQCFIQFL SNPAVTFGTA IAAFYLPVVI MTVLYIHISL ASRSRVHKHR PE GPKEKKA KTKRQMAARE RKVTRTIFAI LLAFILTWTP YNVMVLVNTF CQSCIPDTVW SIGYWLCYVN STINPACYAL CNA TFKKTF RHLLLCQYRN IGTARHHHHH HHH UniProtKB: Muscarinic acetylcholine receptor M4, Muscarinic acetylcholine receptor M4 |
-分子 #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
分子 | 名称: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 38.402867 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: HHHHHHGSSG SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLI IWDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR F LDDNQIVT ...文字列: HHHHHHGSSG SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLI IWDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR F LDDNQIVT SSGDTTCALW DIETGQQTTT FTGHTGDVMS LSLAPDTRLF VSGACDASAK LWDVREGMCR QTFTGHESDI NA ICFFPNG NAFATGSDDA TCRLFDLRAD QELMTYSHDN IICGITSVSF SKSGRLLLAG YDDFNCNVWD ALKADRAGVL AGH DNRVSC LGVTDDGMAV ATGSWDSFLK IWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
分子 | 名称: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 タイプ: protein_or_peptide / ID: 3 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 7.729947 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: ASNNTASIAQ ARKLVEQLKM EANIDRIKVS KAAADLMAYC EAHAKEDPLL TPVPASENPF REKKFFCAIL UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #4: Antibody fragment scFv16
分子 | 名称: Antibody fragment scFv16 / タイプ: protein_or_peptide / ID: 4 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 26.466486 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...文字列: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL K |
-分子 #5: Guanine nucleotide-binding protein G(i) subunit alpha-1
分子 | 名称: Guanine nucleotide-binding protein G(i) subunit alpha-1 タイプ: protein_or_peptide / ID: 5 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() ![]() |
分子量 | 理論値: 40.414047 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...文字列: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHASM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1 |
-分子 #6: xanomeline
分子 | 名称: xanomeline / タイプ: ligand / ID: 6 / コピー数: 2 / 式: XNO |
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分子量 | 理論値: 281.417 Da |
Chemical component information | ![]() ChemComp-XNO: |
-分子 #7: water
分子 | 名称: water / タイプ: ligand / ID: 7 / コピー数: 47 / 式: HOH |
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分子量 | 理論値: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | 単粒子再構成法 |
試料の集合状態 | particle |
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試料調製
緩衝液 | pH: 7.5 |
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凍結 | 凍結剤: ETHANE |
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電子顕微鏡法
顕微鏡 | TFS KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) 平均電子線量: 52.4 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1.5 µm / 最小 デフォーカス(公称値): 0.5 µm |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |