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Yorodumi- EMDB-31479: Cryo-EM structure of human angiotensin receptor AT1R in complex G... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-31479 | |||||||||||||||||||||
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Title | Cryo-EM structure of human angiotensin receptor AT1R in complex Gq proteins and Sar1-AngII | |||||||||||||||||||||
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Sample |
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Keywords | GPCR / angiotensin receptor / MEMBRANE PROTEIN | |||||||||||||||||||||
Function / homology | Function and homology information Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / PLC beta mediated events / entrainment of circadian clock / phospholipase C-activating dopamine receptor signaling pathway / regulation of platelet activation / phototransduction, visible light / 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 / entrainment of circadian clock / phospholipase C-activating dopamine receptor signaling pathway / regulation of platelet activation / phototransduction, visible light / glutamate receptor signaling pathway / regulation of canonical Wnt signaling pathway / action potential / photoreceptor outer segment / GTPase activator activity / G-protein beta/gamma-subunit complex binding / G protein-coupled receptor binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / negative regulation of protein kinase activity / 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 / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / blood coagulation / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / 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 / nuclear membrane / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / protein stabilization / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / GTP binding / protein-containing complex binding / Golgi apparatus / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||||||||||||||
Biological species | Homo sapiens (human) | |||||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||||||||||||||
Authors | Zhang D / Xu L | |||||||||||||||||||||
Funding support | China, 6 items
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Citation | Journal: EMBO J / Year: 2023 Title: Structural insights into angiotensin receptor signaling modulation by balanced and biased agonists. Authors: 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 / Abstract: 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. | |||||||||||||||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_31479.map.gz | 4.5 MB | EMDB map data format | |
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Header (meta data) | emd-31479-v30.xml emd-31479.xml | 16.7 KB 16.7 KB | Display Display | EMDB header |
Images | emd_31479.png | 103.4 KB | ||
Filedesc metadata | emd-31479.cif.gz | 6.6 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-31479 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-31479 | HTTPS FTP |
-Validation report
Summary document | emd_31479_validation.pdf.gz | 357.5 KB | Display | EMDB validaton report |
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Full document | emd_31479_full_validation.pdf.gz | 357.1 KB | Display | |
Data in XML | emd_31479_validation.xml.gz | 6 KB | Display | |
Data in CIF | emd_31479_validation.cif.gz | 6.8 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-31479 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-31479 | HTTPS FTP |
-Related structure data
Related structure data | 7f6gMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_31479.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.014 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Sample components
-Entire : Angiotensin receptor AT1R in complex with Gq proteins and Sar1-AngII
Entire | Name: Angiotensin receptor AT1R in complex with Gq proteins and Sar1-AngII |
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Components |
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-Supramolecule #1: Angiotensin receptor AT1R in complex with Gq proteins and Sar1-AngII
Supramolecule | Name: Angiotensin receptor AT1R in complex with Gq proteins and Sar1-AngII type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 168 KDa |
-Macromolecule #1: Angiotensin receptor AT1R
Macromolecule | Name: Angiotensin receptor AT1R / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 81.574406 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MDYKDDDDKH HHHHHHHHHE NLYFQGKIEE GKLVIWINGD KGYNGLAEVG KKFEKDTGIK VTVEHPDKLE EKFPQVAATG DGPDIIFWA HDRFGGYAQS GLLAEITPDK AFQDKLYPFT WDAVRYNGKL IAYPIAVEAL SLIYNKDLLP NPPKTWEEIP A LDKELKAK ...String: 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 |
-Macromolecule #2: SAR1-AngII
Macromolecule | Name: SAR1-AngII / type: protein_or_peptide / ID: 2 Details: This peptide Sar1-AngII is the ligand of the protein angiotensin receptor. Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 1.004185 KDa |
Sequence | String: (SAR)RVYIHPF |
-Macromolecule #3: Guanine nucleotide-binding protein G(q) subunit alpha
Macromolecule | Name: Guanine nucleotide-binding protein G(q) subunit alpha / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 43.534449 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MHHHHHHHHH HTLESIMACC LSEEAKEARR INDEIERQLR RDKRDARREL KLLLLGTGES GKSTFIKQMR IIHGSGYSDE DKRGFTKLV YQNIFTAMQA MIRAMDTLKI PYKYEHNKAH AQLVREVDVE KVSAFENPYV DAIKSLWNDP GIQECYDRRR E YQLSDSTK ...String: 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 |
-Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 39.086641 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MHHHHHHHHH HGSSGSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQ DGKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY L SCCRFLDD ...String: 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 |
-Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 9.242612 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MHHHHHHHHH HASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 1 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #7: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 7 / Number of copies: 6 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ChemComp-CLR: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 BASE (4k x 4k) / Average electron dose: 64.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: PDB ENTRY |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 2380323 |
Initial angle assignment | Type: OTHER |
Final angle assignment | Type: OTHER |