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- PDB-9bri: Crystal Structure of Human G Protein-Coupled Receptor Kinase 5 in... -

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Basic information

Entry
Database: PDB / ID: 9bri
TitleCrystal Structure of Human G Protein-Coupled Receptor Kinase 5 in Complex with GRL064-22
ComponentsG protein-coupled receptor kinase 5
KeywordsSIGNALING PROTEIN/INHIBITOR / G protein-coupled receptor / GPCR G protein-coupled receptor kinase / GRK kinase / SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


G-protein-coupled receptor kinase / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / tachykinin receptor signaling pathway / regulation of G protein-coupled receptor signaling pathway / fat cell differentiation / regulation of signal transduction / protein kinase C binding / phospholipid binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway ...G-protein-coupled receptor kinase / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / tachykinin receptor signaling pathway / regulation of G protein-coupled receptor signaling pathway / fat cell differentiation / regulation of signal transduction / protein kinase C binding / phospholipid binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Wnt signaling pathway / protein autophosphorylation / G alpha (s) signalling events / nuclear membrane / G alpha (q) signalling events / protein kinase activity / regulation of cell cycle / nuclear speck / G protein-coupled receptor signaling pathway / protein serine/threonine kinase activity / apoptotic process / positive regulation of cell population proliferation / negative regulation of apoptotic process / ATP binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
GPCR kinase / Regulator of G protein signaling domain / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / RGS, subdomain 2 / RGS domain superfamily / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. ...GPCR kinase / Regulator of G protein signaling domain / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / RGS, subdomain 2 / RGS domain superfamily / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
: / G protein-coupled receptor kinase 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsChen, Y. / Tesmer, J.J.G.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL071818 United States
National Institutes of Health/National Center for Research Resources (NIH/NCRR)CA023168 United States
CitationJournal: Eur.J.Med.Chem. / Year: 2025
Title: Design, synthesis, and X-ray structural studies of a series of highly potent, selective, and drug-like G protein-coupled receptor kinase 5 inhibitors.
Authors: Ghosh, A.K. / Chen, Y. / Gadi, R.K. / Sonawane, A. / Gamage, S.P. / Tesmer, J.G.
History
DepositionMay 11, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 19, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: G protein-coupled receptor kinase 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,4622
Polymers68,9321
Non-polymers5311
Water25214
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area25030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)137.850, 137.850, 70.764
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

#1: Protein G protein-coupled receptor kinase 5


Mass: 68931.727 Da / Num. of mol.: 1 / Mutation: D311N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRK5 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): Rosetta / References: UniProt: P34947
#2: Chemical ChemComp-A1AQ8 / (3Z)-3-[(3,5-dimethyl-4-{[(2S)-5-oxooxolane-2-carbonyl]amino}-1H-pyrrol-2-yl)methylidene]-N-[(1R)-1-(4-fluorophenyl)ethyl]-2-oxo-2,3-dihydro-1H-indole-5-carboxamide


Mass: 530.547 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H27FN4O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.44 Å3/Da / Density % sol: 49.56 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop
Details: 220 mM potassium citrate tribasic, 20% PEG3350, crystals soaked in 25% PEG3350, 10% glycerol, 1 mM inhibitor

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.9201 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 17, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.9→29.53 Å / Num. obs: 15665 / % possible obs: 99.8 % / Redundancy: 13.8 % / Biso Wilson estimate: 59.99 Å2 / CC1/2: 0.997 / Net I/σ(I): 13.8
Reflection shellResolution: 2.9→2.97 Å / Num. unique obs: 15481 / CC1/2: 0.9

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
autoPROCdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→29.53 Å / SU ML: 0.3559 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 25.0096
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.26 1564 10 %
Rwork0.2127 14069 -
obs0.2174 15633 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 76.23 Å2
Refinement stepCycle: LAST / Resolution: 2.9→29.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4092 0 39 14 4145
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00344225
X-RAY DIFFRACTIONf_angle_d0.69875689
X-RAY DIFFRACTIONf_chiral_restr0.0396589
X-RAY DIFFRACTIONf_plane_restr0.0046742
X-RAY DIFFRACTIONf_dihedral_angle_d20.24681628
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-2.990.35011390.29861254X-RAY DIFFRACTION99.5
2.99-3.10.32121400.26191255X-RAY DIFFRACTION100
3.1-3.220.30291380.26151248X-RAY DIFFRACTION100
3.22-3.370.3151410.26761266X-RAY DIFFRACTION100
3.37-3.550.31271390.25761253X-RAY DIFFRACTION100
3.55-3.770.2261410.22171266X-RAY DIFFRACTION100
3.77-4.060.24811400.20081263X-RAY DIFFRACTION100
4.06-4.470.2581420.18461278X-RAY DIFFRACTION100
4.47-5.110.22071430.16691290X-RAY DIFFRACTION100
5.11-6.430.24691470.20941313X-RAY DIFFRACTION100
6.43-29.530.24111540.19111383X-RAY DIFFRACTION99.93
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.761978660851.03923137858-1.083601385381.89457607199-0.728983697042.74016052628-0.06253601384810.03350627735110.01852060533920.1777034130660.05247376627670.166746690038-0.261973769784-0.2132594456330.08115885690780.4333130254640.04078002314720.001716690329350.3164123916470.0235568451690.3671497207134.570537334518.659149839712.7372738843
21.3280403821.376948970270.1882094839322.73618682101-0.2475208786131.34149593757-0.09476445670680.1748166897280.0577140140192-0.3685386089370.1099856851880.0654839202580.02883000681830.0202058584155-0.007218728992570.4172183555990.05105585700010.0202265474230.2978202551430.01877595704990.2850976266930.1389967444-2.489246957772.38915897853
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 25 through 225 )25 - 2251 - 201
22chain 'A' and (resid 226 through 542 )226 - 542202 - 503

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