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- PDB-3pvu: Bovine GRK2 in complex with Gbetagamma subunits and a selective k... -

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Basic information

Entry
Database: PDB / ID: 3pvu
TitleBovine GRK2 in complex with Gbetagamma subunits and a selective kinase inhibitor (CMPD101)
Components
  • Beta-adrenergic receptor kinase 1
  • 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
KeywordsTRANSFERASE/SIGNALING PROTEIN/INHIBITOR / Transferase / Serine/threonine-protein kinase / ATP-binding / Inhibitor / Membrane / TRANSFERASE-SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


Calmodulin induced events / negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / beta-adrenergic-receptor kinase / Activation of SMO / Edg-2 lysophosphatidic acid receptor binding / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / alpha-2A adrenergic receptor binding / tachykinin receptor signaling pathway ...Calmodulin induced events / negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / beta-adrenergic-receptor kinase / Activation of SMO / Edg-2 lysophosphatidic acid receptor binding / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / alpha-2A adrenergic receptor binding / tachykinin receptor signaling pathway / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / negative regulation of striated muscle contraction / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Cargo recognition for clathrin-mediated endocytosis / positive regulation of protein localization to cilium / desensitization of G protein-coupled receptor signaling pathway / cytoplasmic side of mitochondrial outer membrane / regulation of the force of heart contraction / Activation of the phototransduction cascade / positive regulation of smoothened signaling pathway / G protein-coupled receptor internalization / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / regulation of signal transduction / cardiac muscle contraction / adenylate cyclase-activating adrenergic receptor signaling pathway / viral genome replication / cell projection / intracellular protein transport / G protein-coupled receptor binding / G protein-coupled acetylcholine receptor signaling pathway / photoreceptor disc membrane / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / sensory perception of taste / presynapse / signaling receptor complex adaptor activity / heart development / retina development in camera-type eye / GTPase binding / phospholipase C-activating G protein-coupled receptor signaling pathway / cell population proliferation / protein phosphorylation / protein kinase activity / postsynapse / G protein-coupled receptor signaling pathway / GTPase activity / synapse / symbiont entry into host cell / protein-containing complex binding / ATP binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Helix Hairpins - #1270 / GPCR kinase / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Regulator of G-protein Signalling 4, domain 2 / Regulator of G-protein Signalling 4; domain 2 / Regulator of G protein signaling domain / RGS domain / RGS domain profile. / Regulator of G protein signalling domain ...Helix Hairpins - #1270 / GPCR kinase / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Regulator of G-protein Signalling 4, domain 2 / Regulator of G-protein Signalling 4; domain 2 / Regulator of G protein signaling domain / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / RGS, subdomain 2 / RGS domain superfamily / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain / PH domain profile. / Pleckstrin homology domain. / YVTN repeat-like/Quinoprotein amine dehydrogenase / Pleckstrin homology domain / 7 Propeller / Methylamine Dehydrogenase; Chain H / Few Secondary Structures / Irregular / 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 / Helix Hairpins / PH-like domain superfamily / WD domain, G-beta repeat / Roll / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Trp-Asp (WD) repeats profile. / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-QRW / Beta-adrenergic receptor kinase 1 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesBos taurus (domestic cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.48 Å
AuthorsThal, D.M. / Tesmer, J.J.
CitationJournal: Mol.Pharmacol. / Year: 2011
Title: Molecular Mechanism of Selectivity among G Protein-Coupled Receptor Kinase 2 Inhibitors.
Authors: Thal, D.M. / Yeow, R.Y. / Schoenau, C. / Huber, J. / Tesmer, J.J.
History
DepositionDec 7, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 1, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 27, 2011Group: Database references
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-adrenergic receptor kinase 1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)126,8694
Polymers126,4023
Non-polymers4661
Water21612
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6510 Å2
ΔGint-49 kcal/mol
Surface area47420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)186.504, 73.502, 121.993
Angle α, β, γ (deg.)90.00, 115.10, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Beta-adrenergic receptor kinase 1 / GRK2 / Beta-ARK-1 / G-protein-coupled receptor kinase 2


Mass: 80578.820 Da / Num. of mol.: 1 / Mutation: S670A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: ADRBK1, GRK2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P21146, beta-adrenergic-receptor kinase
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37416.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62871
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 8406.658 Da / Num. of mol.: 1 / Fragment: UNP residues 1-68
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212
#4: Chemical ChemComp-QRW / 3-({[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]methyl}amino)-N-[2-(trifluoromethyl)benzyl]benzamide


Mass: 466.458 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H21F3N6O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Formula: H2O

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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: 3.03 Å3/Da / Density % sol: 59.47 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.25
Details: 7% PEG3350, 200 mM NaCl, 100 mM MES pH 5.25, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 150 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 1, 2009
RadiationMonochromator: DIAMOND [111] / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.478→30 Å / Num. obs: 51786 / % possible obs: 99.1 % / Observed criterion σ(I): -3 / Redundancy: 6.4 % / Rsym value: 0.085 / Χ2: 1.063 / Net I/σ(I): 16.4
Reflection shell
Resolution (Å)Redundancy (%)Num. unique allΧ2Diffraction-ID% possible allRsym value
2.5-2.596.551491.073198.6
2.59-2.696.550991.055198.6
2.69-2.826.551171.041198.80.92
2.82-2.966.451521.0261990.555
2.96-3.156.451561.0531990.354
3.15-3.396.451461.063199.20.198
3.39-3.736.452101.121199.40.12
3.73-4.276.451841.146199.40.082
4.27-5.386.352321.148199.60.064
5.38-306.253410.902199.60.051

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
REFMAC5.5.0102phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1OMW

1omw


Resolution: 2.48→30 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.927 / WRfactor Rfree: 0.2918 / WRfactor Rwork: 0.2439 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.7738 / SU B: 26.737 / SU ML: 0.263 / SU R Cruickshank DPI: 0.4043 / SU Rfree: 0.2845 / Cross valid method: THROUGHOUT / ESU R Free: 0.284 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2743 2636 5.1 %RANDOM
Rwork0.2264 ---
obs0.2288 49091 96.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 217.68 Å2 / Biso mean: 89.4873 Å2 / Biso min: 48.36 Å2
Baniso -1Baniso -2Baniso -3
1--4.17 Å20 Å2-5.03 Å2
2--5.17 Å20 Å2
3----5.27 Å2
Refinement stepCycle: LAST / Resolution: 2.48→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8086 0 34 12 8132
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0228292
X-RAY DIFFRACTIONr_bond_other_d0.0010.025795
X-RAY DIFFRACTIONr_angle_refined_deg1.131.96211173
X-RAY DIFFRACTIONr_angle_other_deg0.779314032
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.19751003
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.69123.734399
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.759151502
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.2551564
X-RAY DIFFRACTIONr_chiral_restr0.0620.21201
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.029177
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021717
X-RAY DIFFRACTIONr_mcbond_it0.3191.55016
X-RAY DIFFRACTIONr_mcbond_other0.0521.52042
X-RAY DIFFRACTIONr_mcangle_it0.60828065
X-RAY DIFFRACTIONr_scbond_it0.90233276
X-RAY DIFFRACTIONr_scangle_it1.4694.53108
LS refinement shellResolution: 2.478→2.542 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.335 116 -
Rwork0.372 2573 -
all-2689 -
obs--68.72 %
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)
12.10260.5956-0.0411.1326-0.93734.5168-0.07310.17630.4695-0.0149-0.01220.0311-0.1813-0.50170.08540.35870.0265-0.04460.1504-0.05060.321851.468529.265553.247
23.3719-0.11210.60562.13970.31274.31620.2616-0.3082-0.58510.3285-0.168-0.18280.7253-0.2546-0.09360.4675-0.1093-0.20020.0905-0.02910.507145.4899-5.159544.7408
34.87791.61021.98654.90571.8778.33540.322-0.2704-0.26370.3826-0.08370.32761.1004-0.8783-0.23830.4035-0.12460.05670.4767-0.12740.158549.990723.182389.6918
43.77680.08321.94341.36080.48943.4913-0.11310.43310.1541-0.04640.2011-0.2373-0.1080.8432-0.0880.1312-0.07460.09060.227-0.07220.137968.041944.0279111.6865
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A30 - 184
2X-RAY DIFFRACTION1A514 - 545
3X-RAY DIFFRACTION2A185 - 513
4X-RAY DIFFRACTION3A546 - 668
5X-RAY DIFFRACTION4B3 - 340
6X-RAY DIFFRACTION4G8 - 68

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