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Yorodumi- PDB-7w3z: Cryo-EM Structure of Human Gastrin Releasing Peptide Receptor in ... -
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-Basic information
Entry | Database: PDB / ID: 7w3z | |||||||||||||||||||||
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Title | Cryo-EM Structure of Human Gastrin Releasing Peptide Receptor in complex with the agonist Gastrin Releasing Peptide 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 / entrainment of circadian clock / phospholipase C-activating dopamine receptor signaling pathway / regulation of platelet activation ...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 / entrainment of circadian clock / phospholipase C-activating dopamine receptor signaling pathway / regulation of platelet activation / psychomotor behavior / phototransduction, visible light / G protein-coupled peptide receptor activity / neuropeptide binding / regulation of canonical Wnt signaling pathway / motor behavior / glutamate receptor signaling pathway / action potential / social behavior / carbohydrate transmembrane transporter activity / photoreceptor outer segment / GTPase activator activity / G-protein beta/gamma-subunit complex binding / Peptide ligand-binding receptors / 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 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / blood coagulation / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / regulation of cell population proliferation / 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 / periplasmic space / learning or memory / 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 | Escherichia coli (E. coli) Homo sapiens (human) | |||||||||||||||||||||
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 | 7w3z.cif.gz | 252.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7w3z.ent.gz | 192.8 KB | Display | PDB format |
PDBx/mmJSON format | 7w3z.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7w3z_validation.pdf.gz | 734.3 KB | Display | wwPDB validaton report |
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Full document | 7w3z_full_validation.pdf.gz | 743.1 KB | Display | |
Data in XML | 7w3z_validation.xml.gz | 37.7 KB | Display | |
Data in CIF | 7w3z_validation.cif.gz | 58.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/w3/7w3z ftp://data.pdbj.org/pub/pdb/validation_reports/w3/7w3z | HTTPS FTP |
-Related structure data
Related structure data | 32297MC 7w40C 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
#3: 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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#4: 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 |
#5: 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 / Protein/peptide / Antibody , 3 types, 3 molecules ALH
#1: Protein | Mass: 99534.102 Da / Num. of mol.: 1 / Mutation: E198A, N199A, K265A, I157A Source method: isolated from a genetically manipulated source Details: 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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#2: Protein/peptide | Mass: 1375.604 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) |
#6: 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) |
-Details
Has ligand of interest | N |
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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: Human Gastrin Releasing Peptide Receptor in complex with the agonist Gastrin Releasing Peptide and Gq heterotrimers and ScFv16 Type: COMPLEX / Entity ID: all / 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: 2380323 / Symmetry type: POINT |