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Yorodumi- PDB-7w40: Cryo-EM Structure of Human Gastrin Releasing Peptide Receptor in ... -
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-Basic information
Entry | Database: PDB / ID: 7w40 | |||||||||||||||||||||
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Title | Cryo-EM Structure of Human Gastrin Releasing Peptide Receptor in complex with the agonist Bombesin (6-14) [D-Phe6, beta-Ala11, Phe13, Nle14] and Gq heterotrimers | |||||||||||||||||||||
Components |
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Keywords | MEMBRANE PROTEIN / GPCR / Gastrin Releasing Peptide Receptor | |||||||||||||||||||||
Function / homology | Function and homology information response to external biotic stimulus / positive regulation of respiratory gaseous exchange / positive regulation of behavioral fear response / neuropeptide receptor activity / 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 / psychomotor behavior ...response to external biotic stimulus / positive regulation of respiratory gaseous exchange / positive regulation of behavioral fear response / neuropeptide receptor activity / 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 / psychomotor behavior / phototransduction, visible light / entrainment of circadian clock / neuropeptide binding / G protein-coupled peptide receptor activity / glutamate receptor signaling pathway / regulation of canonical Wnt signaling pathway / motor behavior / action potential / social behavior / : / carbohydrate transmembrane transporter activity / photoreceptor outer segment / Peptide ligand-binding receptors / 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 / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / regulation of cell population proliferation / 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 / periplasmic space / learning or memory / 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 Similarity search - Function | |||||||||||||||||||||
Biological species | Escherichia coli (E. coli) Homo sapiens (human) synthetic construct (others) | |||||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å | |||||||||||||||||||||
Authors | Zhan, Y. / Peng, S. / Zhang, H. | |||||||||||||||||||||
Funding support | China, 6items
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Citation | Journal: Proc Natl Acad Sci U S A / Year: 2023 Title: Structures of human gastrin-releasing peptide receptors bound to antagonist and agonist for cancer and itch therapy. Authors: Shuman Peng / Yuting Zhan / Dongqi Zhang / Lu Ren / Anqi Chen / Zhou-Feng Chen / Haitao Zhang / Abstract: Gastrin releasing peptide receptor (GRPR), a member of the bombesin (BBN) G protein-coupled receptors, is aberrantly overexpressed in several malignant tumors, including those of the breast, ...Gastrin releasing peptide receptor (GRPR), a member of the bombesin (BBN) G protein-coupled receptors, is aberrantly overexpressed in several malignant tumors, including those of the breast, prostate, pancreas, lung, and central nervous system. Additionally, it also mediates non-histaminergic itch and pathological itch conditions in mice. Thus, GRPR could be an attractive target for cancer and itch therapy. Here, we report the inactive state crystal structure of human GRPR in complex with the non-peptide antagonist PD176252, as well as two active state cryo-electron microscopy (cryo-EM) structures of GRPR bound to the endogenous peptide agonist gastrin-releasing peptide and the synthetic BBN analog [D-Phe, β-Ala, Phe, Nle] Bn (6-14), in complex with G heterotrimers. These structures revealed the molecular mechanisms for the ligand binding, receptor activation, and G proteins signaling of GRPR, which are expected to accelerate the structure-based design of GRPR antagonists and agonists for the treatments of cancer and pruritus. | |||||||||||||||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7w40.cif.gz | 235.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7w40.ent.gz | 176.9 KB | Display | PDB format |
PDBx/mmJSON format | 7w40.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7w40_validation.pdf.gz | 754.6 KB | Display | wwPDB validaton report |
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Full document | 7w40_full_validation.pdf.gz | 765.2 KB | Display | |
Data in XML | 7w40_validation.xml.gz | 36.5 KB | Display | |
Data in CIF | 7w40_validation.cif.gz | 56.5 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/w4/7w40 ftp://data.pdbj.org/pub/pdb/validation_reports/w4/7w40 | HTTPS FTP |
-Related structure data
Related structure data | 32298MC 7w3zC 7w41C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules BCD
#2: Protein | Mass: 41194.844 Da / Num. of mol.: 1 / Mutation: R183Q, Q209L Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAQ, GAQ / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P50148 |
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#3: Protein | Mass: 41398.137 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873 |
#4: Protein | Mass: 9242.612 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768 |
-Protein / Antibody / Protein/peptide , 3 types, 3 molecules AHE
#1: Protein | Mass: 99534.102 Da / Num. of mol.: 1 / Mutation: E198A, N199A, K265A, I157A Source method: isolated from a genetically manipulated source Details: The fusion protein of Maltodextrin-binding, protein,HiBit expression tag and Gastrin-releasing peptide receptor Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human) Gene: malE, GRW33_05015, GRPR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A6D0N546, UniProt: P30550 |
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#5: Antibody | Mass: 32785.582 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm) |
#6: Protein/peptide | Mass: 1118.307 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Peptide Receptor in complex with the agonist Bombesin (6-14) [D-Phe6, beta-Ala11, Phe13, Nle14] and Gq heterotrimers and ScFv16 Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 64 e/Å2 / Film or detector model: GATAN K2 BASE (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.18.2_3874: / Classification: refinement |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
3D reconstruction | Resolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1380329 / Symmetry type: POINT |