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- PDB-7w41: Crystal Structure of Human Gastrin Releasing Peptide Receptor in ... -

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Basic information

Entry
Database: PDB / ID: 7w41
TitleCrystal Structure of Human Gastrin Releasing Peptide Receptor in complex with the antagonist PD176252
ComponentsGastrin-releasing peptide receptor,GlgA glycogen synthase
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 / alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity / neuropeptide receptor activity / psychomotor behavior / neuropeptide binding / G protein-coupled peptide receptor activity / motor behavior / social behavior ...response to external biotic stimulus / positive regulation of respiratory gaseous exchange / positive regulation of behavioral fear response / alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity / neuropeptide receptor activity / psychomotor behavior / neuropeptide binding / G protein-coupled peptide receptor activity / motor behavior / social behavior / Peptide ligand-binding receptors / regulation of cell population proliferation / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / learning or memory / G protein-coupled receptor signaling pathway / plasma membrane
Similarity search - Function
Gastrin-releasing peptide receptor / Bombesin receptor-like / Glycosyl transferases group 1 / Bacterial/plant glycogen synthase / Starch synthase, catalytic domain / Starch synthase catalytic domain / Glycogen Phosphorylase B; / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like ...Gastrin-releasing peptide receptor / Bombesin receptor-like / Glycosyl transferases group 1 / Bacterial/plant glycogen synthase / Starch synthase, catalytic domain / Starch synthase catalytic domain / Glycogen Phosphorylase B; / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-8B8 / Gastrin-releasing peptide receptor / Glycogen synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
Pyrococcus abyssi GE5 (archaea)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.952 Å
AuthorsPeng, S. / Zhan, Y. / 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 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Gastrin-releasing peptide receptor,GlgA glycogen synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,9592
Polymers54,3751
Non-polymers5851
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area24240 Å2
Unit cell
Length a, b, c (Å)134.104, 60.025, 98.489
Angle α, β, γ (deg.)90.000, 113.573, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Gastrin-releasing peptide receptor,GlgA glycogen synthase / GRP-R / GRP-preferring bombesin receptor / Glycogen synthase


Mass: 54374.758 Da / Num. of mol.: 1 / Mutation: S127K,I157A,R259E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Pyrococcus abyssi GE5 (archaea)
Gene: GRPR, PAB2292 / Strain: GE5 / Orsay / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P30550, UniProt: Q9V2J8
#2: Chemical ChemComp-8B8 / (2S)-3-(1H-indol-3-yl)-N-[[1-(5-methoxypyridin-2-yl)cyclohexyl]methyl]-2-methyl-2-[(4-nitrophenyl)carbamoylamino]propanamide


Mass: 584.665 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H36N6O5 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.34 Å3/Da / Density % sol: 57.4 %
Crystal growTemperature: 294 K / Method: lipidic cubic phase / pH: 6.8
Details: 100mM MES, pH 6.8, 300mM Ammonium dihydrogen phosphate, 28% PEG 400, 5% polypropylene glycol P 400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 1.033 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Nov 14, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 2.95→27.767 Å / Num. obs: 14852 / % possible obs: 96.9 % / Redundancy: 4 % / Rmerge(I) obs: 0.151 / Net I/σ(I): 8.14
Reflection shellResolution: 2.95→3.06 Å / Rmerge(I) obs: 0.599 / Num. unique obs: 1449

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7F6G

7f6g


Resolution: 2.952→27.767 Å / Cor.coef. Fo:Fc: 0.907 / Cor.coef. Fo:Fc free: 0.878 / SU B: 0.1 / SU ML: 0 / Cross valid method: FREE R-VALUE / ESU R: 0.465 / ESU R Free: 0.532
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.3205 1488 10.019 %
Rwork0.2801 13364 -
all0.284 --
obs-14852 96.888 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 70 Å2
Baniso -1Baniso -2Baniso -3
1--0.028 Å20 Å20.013 Å2
2--0.053 Å2-0 Å2
3----0.027 Å2
Refinement stepCycle: LAST / Resolution: 2.952→27.767 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3814 0 43 0 3857
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.952-3.0290.395700.38622X-RAY DIFFRACTION62.4549
3.029-3.1120.3681120.368998X-RAY DIFFRACTION99.5516
3.112-3.2020.4181050.341954X-RAY DIFFRACTION99.9057
3.202-3.30.3481030.345921X-RAY DIFFRACTION99.8051
3.3-3.4080.385990.32897X-RAY DIFFRACTION99.6997
3.408-3.5280.384990.321886X-RAY DIFFRACTION100
3.528-3.6610.306930.299841X-RAY DIFFRACTION100
3.661-3.810.327890.291795X-RAY DIFFRACTION99.7743
3.81-3.9790.326870.282791X-RAY DIFFRACTION100
3.979-4.1730.343830.264733X-RAY DIFFRACTION99.8776
4.173-4.3980.314780.266711X-RAY DIFFRACTION100
4.398-4.6640.29770.267693X-RAY DIFFRACTION100
4.664-4.9850.263710.259632X-RAY DIFFRACTION100
4.985-5.3830.414650.303583X-RAY DIFFRACTION99.8459
5.383-5.8950.384610.301552X-RAY DIFFRACTION100
5.895-6.5870.319560.319507X-RAY DIFFRACTION100
6.587-7.60.33500.266442X-RAY DIFFRACTION99.7972
7.6-80.224400.179369X-RAY DIFFRACTION99.7561
8-9.2910.236330.192293X-RAY DIFFRACTION98.4894
9.291-100.284170.284144X-RAY DIFFRACTION80.9045

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