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基本情報
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タイトル | Cryo-EM structure of human angiotensin receptor AT1R in complex Gq proteins and Sar1-AngII | |||||||||||||||||||||
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![]() | GPCR / angiotensin receptor / MEMBRANE PROTEIN | |||||||||||||||||||||
機能・相同性 | ![]() Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway / regulation of platelet activation / phototransduction, visible light / entrainment of circadian clock / glutamate receptor signaling pathway / regulation of canonical Wnt signaling pathway / action potential ...Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway / regulation of platelet activation / phototransduction, visible light / entrainment of circadian clock / glutamate receptor signaling pathway / regulation of canonical Wnt signaling pathway / action potential / : / photoreceptor outer segment / GTPase activator activity / G protein-coupled receptor binding / negative regulation of protein kinase activity / G-protein beta/gamma-subunit complex binding / 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 activation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / 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 / blood coagulation / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / nuclear membrane / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / protein stabilization / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / GTP binding / Golgi apparatus / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytoplasm / cytosol 類似検索 - 分子機能 | |||||||||||||||||||||
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手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.9 Å | |||||||||||||||||||||
![]() | Zhang D / Xu L | |||||||||||||||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structural insights into angiotensin receptor signaling modulation by balanced and biased agonists. 著者: Dongqi Zhang / Yongfeng Liu / Saheem A Zaidi / Lingyi Xu / Yuting Zhan / Anqi Chen / Jiangtao Guo / Xi-Ping Huang / Bryan L Roth / Vsevolod Katritch / Vadim Cherezov / Haitao Zhang / ![]() ![]() 要旨: The peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT R and its downstream signaling proteins G and β-arrestin. AT R blockers, clinically ...The peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT R and its downstream signaling proteins G and β-arrestin. AT R blockers, clinically used as antihypertensive drugs, inhibit both signaling pathways, whereas AT R β-arrestin-biased agonists have shown great potential for the treatment of acute heart failure. Here, we present a cryo-electron microscopy (cryo-EM) structure of the human AT R in complex with a balanced agonist, Sar -AngII, and G protein at 2.9 Å resolution. This structure, together with extensive functional assays and computational modeling, reveals the molecular mechanisms for AT R signaling modulation and suggests that a major hydrogen bond network (MHN) inside the receptor serves as a key regulator of AT R signal transduction from the ligand-binding pocket to both G and β-arrestin pathways. Specifically, we found that the MHN mutations N111 A and N294 A induce biased signaling to G and β-arrestin, respectively. These insights should facilitate AT R structure-based drug discovery for the treatment of cardiovascular diseases. | |||||||||||||||||||||
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-検証レポート
文書・要旨 | ![]() | 357.5 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 357.1 KB | 表示 | |
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CIF形式データ | ![]() | 6.8 KB | 表示 | |
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-関連構造データ
関連構造データ | ![]() 7f6gMC 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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ボクセルのサイズ | X=Y=Z: 1.014 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
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試料の構成要素
-全体 : Angiotensin receptor AT1R in complex with Gq proteins and Sar1-AngII
全体 | 名称: Angiotensin receptor AT1R in complex with Gq proteins and Sar1-AngII |
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要素 |
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-超分子 #1: Angiotensin receptor AT1R in complex with Gq proteins and Sar1-AngII
超分子 | 名称: Angiotensin receptor AT1R in complex with Gq proteins and Sar1-AngII 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: ![]() |
分子量 | 理論値: 168 KDa |
-分子 #1: Angiotensin receptor AT1R
分子 | 名称: Angiotensin receptor AT1R / 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: 81.574406 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MDYKDDDDKH HHHHHHHHHE NLYFQGKIEE GKLVIWINGD KGYNGLAEVG KKFEKDTGIK VTVEHPDKLE EKFPQVAATG DGPDIIFWA HDRFGGYAQS GLLAEITPDK AFQDKLYPFT WDAVRYNGKL IAYPIAVEAL SLIYNKDLLP NPPKTWEEIP A LDKELKAK ...文字列: MDYKDDDDKH HHHHHHHHHE NLYFQGKIEE GKLVIWINGD KGYNGLAEVG KKFEKDTGIK VTVEHPDKLE EKFPQVAATG DGPDIIFWA HDRFGGYAQS GLLAEITPDK AFQDKLYPFT WDAVRYNGKL IAYPIAVEAL SLIYNKDLLP NPPKTWEEIP A LDKELKAK GKSALMFNLQ EPYFTWPLIA ADGGYAFKYA AGKYDIKDVG VDNAGAKAGL TFLVDLIKNK HMNADTDYSI AE AAFNKGE TAMTINGPWA WSNIDTSAVN YGVTVLPTFK GQPSKPFVGV LSAGINAASP NKELAKEFLE NYLLTDEGLE AVN KDKPLG AVALKSYEEE LAKDPRIAAT MENAQKGEIM PNIPQMSAFW YAVRTAVINA ASGRQTVDEA LKDAQTILNS STED GIKRI QDDCPKAGRH NYIFVMIPTL YSIIFVVGIF GNSLVVIVIY FYMKLKTVAS VFLLNLALAD LCALLTLPLW AVYTA MEYR WPFGNYLCKI ASASVSFNLY ASVFLLTCLS IDRYLAIVHP MKSRLRRTML VAKVTCIIIW LLAGLASLPA IIHRNV FFI ENTNITVCAF HYESQNSTLP IGLGLTKNIL GFLFPFLIIL TSYTLIWKAL KKAYEIQKNK PRNDDIFKII MAIVLFF FF SWIPHQIFTF LDVLIQLGII RDCRIADIVD TAMPITICIA YFNACLNPLF YGFLGKKFKR YFLQLLKYIP PKAKSHSN L STKM |
-分子 #2: SAR1-AngII
分子 | 名称: SAR1-AngII / タイプ: protein_or_peptide / ID: 2 詳細: This peptide Sar1-AngII is the ligand of the protein angiotensin receptor. 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: 1.004185 KDa |
配列 | 文字列: (SAR)RVYIHPF |
-分子 #3: Guanine nucleotide-binding protein G(q) subunit alpha
分子 | 名称: Guanine nucleotide-binding protein G(q) subunit alpha 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: 43.534449 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MHHHHHHHHH HTLESIMACC LSEEAKEARR INDEIERQLR RDKRDARREL KLLLLGTGES GKSTFIKQMR IIHGSGYSDE DKRGFTKLV YQNIFTAMQA MIRAMDTLKI PYKYEHNKAH AQLVREVDVE KVSAFENPYV DAIKSLWNDP GIQECYDRRR E YQLSDSTK ...文字列: MHHHHHHHHH HTLESIMACC LSEEAKEARR INDEIERQLR RDKRDARREL KLLLLGTGES GKSTFIKQMR IIHGSGYSDE DKRGFTKLV YQNIFTAMQA MIRAMDTLKI PYKYEHNKAH AQLVREVDVE KVSAFENPYV DAIKSLWNDP GIQECYDRRR E YQLSDSTK YYLNDLDRVA DPAYLPTQQD VLRVQVPTTG IIEYPFDLQS VIFRMVDVGG LRSERRKWIH CFENVTSIMF LV ALSEYDQ VLVESDNENR MEESKALFRT IITYPWFQNS SVILFLNKKD LLEEKIMYSH LVDYFPEYDG PQRDAQAARE FIL KMFVDL NPDSDKIIYS HFTCATDTEN IRFVFAAVKD TILQLNLKEY NLV UniProtKB: Guanine nucleotide-binding protein G(q) subunit alpha |
-分子 #4: 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: 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: 39.086641 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MHHHHHHHHH HGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQ DGKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY L SCCRFLDD ...文字列: MHHHHHHHHH HGSSGSELDQ 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 UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-分子 #5: 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: 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: 9.242612 KDa |
組換発現 | 生物種: ![]() ![]() |
配列 | 文字列: MHHHHHHHHH HASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-分子 #6: 2-acetamido-2-deoxy-beta-D-glucopyranose
分子 | 名称: 2-acetamido-2-deoxy-beta-D-glucopyranose / タイプ: ligand / ID: 6 / コピー数: 1 / 式: NAG |
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分子量 | 理論値: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-分子 #7: CHOLESTEROL
分子 | 名称: CHOLESTEROL / タイプ: ligand / ID: 7 / コピー数: 6 / 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
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 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K2 BASE (4k x 4k) 平均電子線量: 64.0 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: OTHER / 撮影モード: BRIGHT FIELD |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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画像解析
初期モデル | モデルのタイプ: PDB ENTRY |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 2.9 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 2380323 |
初期 角度割当 | タイプ: OTHER |
最終 角度割当 | タイプ: OTHER |