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- PDB-7w3z: Cryo-EM Structure of Human Gastrin Releasing Peptide Receptor in ... -

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Basic information

Entry
Database: PDB / ID: 7w3z
TitleCryo-EM Structure of Human Gastrin Releasing Peptide Receptor in complex with the agonist Gastrin Releasing Peptide and Gq heterotrimers
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Gastrin Releasing Peptide PRGNHWAVGHLM(NH2)
  • Maltodextrin-binding protein,Gastrin-releasing peptide receptor
  • ScFv16
KeywordsMEMBRANE 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 / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / neuropeptide receptor activity / sensory perception of itch / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / phospholipase C-activating serotonin receptor signaling pathway / PLC beta mediated events ...response to external biotic stimulus / positive regulation of respiratory gaseous exchange / positive regulation of behavioral fear response / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / neuropeptide receptor activity / sensory perception of itch / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / phospholipase C-activating serotonin receptor signaling pathway / PLC beta mediated events / regulation of platelet activation / entrainment of circadian clock / psychomotor behavior / G protein-coupled peptide receptor activity / regulation of canonical Wnt signaling pathway / neuropeptide binding / glutamate receptor signaling pathway / mast cell degranulation / motor behavior / phototransduction, visible light / carbohydrate transmembrane transporter activity / photoreceptor outer segment / social behavior / postsynaptic cytosol / cellular response to acidic pH / hormone-mediated signaling pathway / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / Peptide ligand-binding receptors / GTPase activator activity / neuropeptide signaling pathway / response to prostaglandin E / G protein-coupled receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / blood coagulation / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / regulation of cell population proliferation / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / sensory perception of taste / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / retina development in camera-type eye / GTPase binding / G protein activity / fibroblast proliferation / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / nuclear membrane / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / learning or memory / periplasmic space / 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
Similarity search - Function
Gastrin-releasing peptide receptor / Bombesin receptor-like / G-protein alpha subunit, group Q / GI Alpha 1, domain 2-like / GI Alpha 1, domain 2-like / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein ...Gastrin-releasing peptide receptor / Bombesin receptor-like / G-protein alpha subunit, group Q / GI Alpha 1, domain 2-like / GI Alpha 1, domain 2-like / Maltose/Cyclodextrin ABC transporter, substrate-binding protein / Solute-binding family 1, conserved site / Bacterial extracellular solute-binding proteins, family 1 signature. / Bacterial extracellular solute-binding protein / Bacterial extracellular solute-binding protein / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Maltodextrin-binding protein / Gastrin-releasing peptide receptor / Guanine nucleotide-binding protein G(q) subunit alpha / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsZhan, Y. / Peng, S. / Zhang, H.
Funding support China, 6items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2018YFA0508100 China
National Natural Science Foundation of China (NSFC)81722044 China
National Natural Science Foundation of China (NSFC)91753115 China
National Natural Science Foundation of China (NSFC)21778049 China
National Natural Science Foundation of China (NSFC)81861148018 China
Ministry of Science and Technology (MoST, China)2018ZX09711002 China
CitationJournal: 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
DepositionNov 26, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 22, 2023Provider: repository / Type: Initial release
Revision 1.0Feb 22, 2023Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 22, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 22, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Feb 22, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 22, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Jul 2, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Maltodextrin-binding protein,Gastrin-releasing peptide receptor
L: Gastrin Releasing Peptide PRGNHWAVGHLM(NH2)
B: Guanine nucleotide-binding protein G(q) subunit alpha
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
H: ScFv16


Theoretical massNumber of molelcules
Total (without water)225,5316
Polymers225,5316
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules BCD

#3: Protein Guanine nucleotide-binding protein G(q) subunit alpha / Guanine nucleotide-binding protein alpha-q


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
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


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 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


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

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Protein / Protein/peptide / Antibody , 3 types, 3 molecules ALH

#1: Protein Maltodextrin-binding protein,Gastrin-releasing peptide receptor / GRP-R / GRP-preferring bombesin receptor


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
#2: Protein/peptide Gastrin Releasing Peptide PRGNHWAVGHLM(NH2)


Mass: 1375.604 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#6: Antibody ScFv16


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)

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: 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
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 64 e/Å2 / Film or detector model: GATAN K2 BASE (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2380323 / Symmetry type: POINT

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