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基本情報
登録情報 | データベース: EMDB / ID: EMD-20470 | |||||||||||||||||||||
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タイトル | Cryo-EM structure of human cannabinoid receptor 2-Gi protein in complex with agonist WIN 55,212-2 | |||||||||||||||||||||
![]() | human cannabinoid receptor 2-Gi protein in complex with agonist WIN 55,212-2 | |||||||||||||||||||||
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機能・相同性 | ![]() 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) / regulation of metabolic process / leukocyte chemotaxis / extrinsic component of cytoplasmic side of plasma membrane / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / Adenylate cyclase inhibitory pathway ...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) / regulation of metabolic process / leukocyte chemotaxis / extrinsic component of cytoplasmic side of plasma membrane / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / response to amphetamine / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Regulation of insulin secretion / G protein-coupled receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / response to peptide hormone / 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 / GDP binding / 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 / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / perikaryon / Extra-nuclear estrogen signaling / cell population proliferation / response to lipopolysaccharide / inflammatory response / immune response / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / dendrite / protein-containing complex binding / nucleolus / GTP binding / magnesium ion binding / signal transduction / endoplasmic reticulum / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytoplasm / cytosol 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: 3.2 Å | |||||||||||||||||||||
![]() | Xu TH / Xing C / Zhuang Y / Feng Z / Zhou XE / Chen M / Wang L / Meng X / Xue Y / Wang J ...Xu TH / Xing C / Zhuang Y / Feng Z / Zhou XE / Chen M / Wang L / Meng X / Xue Y / Wang J / Liu H / McGuire T / Zhao G / Melcher K / Zhang C / Xu HE / Xie XQ | |||||||||||||||||||||
資金援助 | ![]() ![]()
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![]() | ![]() タイトル: Cryo-EM Structure of the Human Cannabinoid Receptor CB2-G Signaling Complex. 著者: Changrui Xing / Youwen Zhuang / Ting-Hai Xu / Zhiwei Feng / X Edward Zhou / Maozi Chen / Lei Wang / Xing Meng / Ying Xue / Junmei Wang / Heng Liu / Terence Francis McGuire / Gongpu Zhao / ...著者: Changrui Xing / Youwen Zhuang / Ting-Hai Xu / Zhiwei Feng / X Edward Zhou / Maozi Chen / Lei Wang / Xing Meng / Ying Xue / Junmei Wang / Heng Liu / Terence Francis McGuire / Gongpu Zhao / Karsten Melcher / Cheng Zhang / H Eric Xu / Xiang-Qun Xie / ![]() ![]() 要旨: Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders, inflammation, and pain while avoiding psychotropic side effects mediated by CB1. The mechanisms underlying CB2 ...Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders, inflammation, and pain while avoiding psychotropic side effects mediated by CB1. The mechanisms underlying CB2 activation and signaling are poorly understood but critical for drug design. Here we report the cryo-EM structure of the human CB2-G signaling complex bound to the agonist WIN 55,212-2. The 3D structure reveals the binding mode of WIN 55,212-2 and structural determinants for distinguishing CB2 agonists from antagonists, which are supported by a pair of rationally designed agonist and antagonist. Further structural analyses with computational docking results uncover the differences between CB2 and CB1 in receptor activation, ligand recognition, and G coupling. These findings are expected to facilitate rational structure-based discovery of drugs targeting the cannabinoid system. | |||||||||||||||||||||
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構造の表示
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構造ビューア | EMマップ: ![]() ![]() ![]() |
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マップデータ | ![]() | 3.9 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 18.8 KB 18.8 KB | 表示 表示 | ![]() |
FSC (解像度算出) | ![]() | 6.8 KB | 表示 | ![]() |
画像 | ![]() | 46.1 KB | ||
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「今月の分子」の関連する項目 |
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ファイル | ![]() | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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注釈 | human cannabinoid receptor 2-Gi protein in complex with agonist WIN 55,212-2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.029 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
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試料の構成要素
-全体 : human cannabinoid receptor 2-Gi protein
全体 | 名称: human cannabinoid receptor 2-Gi protein |
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要素 |
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-超分子 #1: human cannabinoid receptor 2-Gi protein
超分子 | 名称: human cannabinoid receptor 2-Gi protein / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#5 |
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由来(天然) | 生物種: ![]() |
組換発現 | 生物種: ![]() ![]() |
-分子 #1: Cannabinoid receptor 2
分子 | 名称: Cannabinoid receptor 2 / 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: 40.76482 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MEECWVTEIA NGSKDGLDSN PMKDYMILSG PQKTAVAVLC TLLGLLSALE NVAVLYLILS SHQLRRKPSY LFIGSLAGAD FLASVVFAC SFVNFHVFHG VDSKAVFLLK IGSVTMTFTA SVGSLLLTAI DRYLCLRYPP SYKALLTRGR ALVTLGIMWV L SALVSYLP ...文字列: MEECWVTEIA NGSKDGLDSN PMKDYMILSG PQKTAVAVLC TLLGLLSALE NVAVLYLILS SHQLRRKPSY LFIGSLAGAD FLASVVFAC SFVNFHVFHG VDSKAVFLLK IGSVTMTFTA SVGSLLLTAI DRYLCLRYPP SYKALLTRGR ALVTLGIMWV L SALVSYLP LMGWTCCPRP CSELFPLIPN DYLLSWLLFI AFLFSGIIYT YGHVLWKAHQ HVASLSGHQD RQVPGMARMR LD VRLAKTL GLVLAVLLIC WFPVLALMAH SLATTLSDQV KKAFAFCSML CLINSMVNPV IYALRSGEIR SSAHHCLAHW KKC VRGLGS EAKEEAPRSS VTETEADGKI TPWPDSRDLD LSDCAAAHHH HHH |
-分子 #2: 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: 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: 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 |
-分子 #3: 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: 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: 39.151855 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MHHHHHHHHM GSLLQSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQ DGKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY L SCCRFLDD ...文字列: MHHHHHHHHM GSLLQSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQ DGKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY L SCCRFLDD NQIVTSSGDT TCALWDIETG QQTTTFTGHT GDVMSLSLAP DTRLFVSGAC DASAKLWDVR EGMCRQTFTG HE SDINAIC FFPNGNAFAT GSDDATCRLF DLRADQELMT YSHDNIICGI TSVSFSKSGR LLLAGYDDFN CNVWDALKAD RAG VLAGHD NRVSCLGVTD DGMAVATGSW DSFLKIWN |
-分子 #4: 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: 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: 7.56375 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFC |
-分子 #5: scFv16
分子 | 名称: scFv16 / 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: synthetic construct (人工物) |
分子量 | 理論値: 27.784896 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 KAAAHHHHHH HH |
-分子 #6: {(3R)-5-methyl-3-[(morpholin-4-yl)methyl]-2,3-dihydro[1,4]oxazino...
分子 | 名称: {(3R)-5-methyl-3-[(morpholin-4-yl)methyl]-2,3-dihydro[1,4]oxazino[2,3,4-hi]indol-6-yl}(naphthalen-1-yl)methanone タイプ: ligand / ID: 6 / コピー数: 1 / 式: WI5 |
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分子量 | 理論値: 426.507 Da |
Chemical component information | ![]() ChemComp-WI5: |
-分子 #7: PALMITIC ACID
分子 | 名称: PALMITIC ACID / タイプ: ligand / ID: 7 / コピー数: 4 / 式: PLM |
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分子量 | 理論値: 256.424 Da |
Chemical component information | ![]() ChemComp-PLM: |
-分子 #8: CHOLESTEROL
分子 | 名称: CHOLESTEROL / タイプ: ligand / ID: 8 / コピー数: 4 / 式: CLR |
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分子量 | 理論値: 386.654 Da |
Chemical component information | ![]() ChemComp-CLR: |
-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
濃度 | 7 mg/mL |
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緩衝液 | pH: 7.2 |
グリッド | モデル: Quantifoil R1.2/1.3 / 材質: GOLD / メッシュ: 300 / 前処理 - タイプ: GLOW DISCHARGE |
凍結 | 凍結剤: ETHANE / チャンバー内湿度: 100 % / チャンバー内温度: 281 K / 装置: FEI VITROBOT MARK IV |
詳細 | Cryo-EM structure of human cannabinoid receptor 2-Gi protein in complex agonist WIN 55,212-2 |
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電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) 検出モード: COUNTING / 実像数: 8810 / 平均露光時間: 8.0 sec. / 平均電子線量: 2.08 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 / Cs: 2.7 mm |
試料ステージ | ホルダー冷却材: NITROGEN |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |