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- PDB-5he2: Bovine GRK2 in complex with Gbetagamma subunits and CCG224406 -

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Basic information

Entry
Database: PDB / ID: 5he2
TitleBovine GRK2 in complex with Gbetagamma subunits and CCG224406
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/TRANSFERASE INHIBITOR / RGS / kinase / PH / WD-40 / inhibitor complex / TRANSFERASE-TRANSFERASE 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 / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / Edg-2 lysophosphatidic acid receptor binding / 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 / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / Edg-2 lysophosphatidic acid receptor binding / alpha-2A adrenergic receptor binding / tachykinin receptor signaling pathway / negative regulation of striated muscle contraction / positive regulation of protein localization to cilium / Cargo recognition for clathrin-mediated endocytosis / desensitization of G protein-coupled receptor signaling pathway / cytoplasmic side of mitochondrial outer membrane / regulation of the force of heart contraction / positive regulation of smoothened signaling pathway / G protein-coupled receptor internalization / G alpha (s) signalling events / G alpha (q) signalling events / regulation of signal transduction / cardiac muscle contraction / viral genome replication / cell projection / intracellular protein transport / G protein-coupled receptor binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / 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 / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / presynapse / Thrombin signalling through proteinase activated receptors (PARs) / peptidyl-serine phosphorylation / heart development / GTPase binding / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / postsynapse / protein kinase activity / protein phosphorylation / G protein-coupled receptor signaling pathway / symbiont entry into host cell / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / ATP binding / membrane / plasma membrane / cytosol / cytoplasm
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. / Pleckstrin homology domain / YVTN repeat-like/Quinoprotein amine dehydrogenase / 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 / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / Helix Hairpins / PH-like domain superfamily / G-protein beta WD-40 repeat / Roll / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Phosphorylase Kinase; domain 1 / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / WD40 repeats / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / 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-F0S / 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
Similarity search - Component
Biological speciesBos taurus (domestic cattle)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.79 Å
AuthorsCato, M.C. / Waninger-Saroni, J. / Tesmer, J.J.G.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL071818 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL086865 United States
American Heart AssociationN014938 United States
American Heart Association15PRE22730028 United States
Michigan Economic Development Corporation and Michigan Technology Tri-Corridor Grant085P1000817 United States
CitationJournal: J.Med.Chem. / Year: 2016
Title: Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors.
Authors: Waldschmidt, H.V. / Homan, K.T. / Cruz-Rodriguez, O. / Cato, M.C. / Waninger-Saroni, J. / Larimore, K.M. / Cannavo, A. / Song, J. / Cheung, J.Y. / Kirchhoff, P.D. / Koch, W.J. / Tesmer, J.J. / Larsen, S.D.
History
DepositionJan 5, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 11, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Mar 6, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)120,4514
Polymers119,8933
Non-polymers5591
Water55831
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6750 Å2
ΔGint-48 kcal/mol
Surface area47590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.729, 241.950, 213.668
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 74762.086 Da / Num. of mol.: 1 / Fragment: UNP residues 30-670 / Mutation: S670A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: ADRBK1, GRK2 / Plasmid: pFastBacDual / Production host: Trichoplusia ni (cabbage looper)
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: 37285.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Plasmid: pFastBacDual / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7845.078 Da / Num. of mol.: 1 / Mutation: C68S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Plasmid: pFastBacDual / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768
#4: Chemical ChemComp-F0S / (4~{S})-4-[3-[(2,6-dimethoxyphenyl)methylcarbamoyl]-4-fluoranyl-phenyl]-~{N}-(1~{H}-indazol-5-yl)-6-methyl-2-oxidanylidene-3,4-dihydro-1~{H}-pyrimidine-5-carboxamide


Mass: 558.560 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H27FN6O5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / 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: 3.42 Å3/Da / Density % sol: 64.03 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 50 mM MES, 0.8-1.2 M sodium chloride, 8-16% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97857 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 16, 2015
RadiationMonochromator: diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 2.8→30 Å / Num. obs: 37227 / % possible obs: 94 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.055 / Rpim(I) all: 0.03 / Rrim(I) all: 0.063 / Χ2: 1.226 / Net I/av σ(I): 20.268 / Net I/σ(I): 13 / Num. measured all: 133864
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.8-2.852.70.7616550.7220.5370.9360.76584.5
2.85-2.92.70.68816810.7620.4850.8460.81285.5
2.9-2.962.70.47116910.8560.3270.5770.78187.3
2.96-3.022.80.37417450.9180.2580.4570.82289.8
3.02-3.082.80.29417720.9450.20.3570.80490.8
3.08-3.152.90.2318040.960.1540.2790.89792.1
3.15-3.2330.17918290.9770.1180.2160.93893.1
3.23-3.323.10.14418370.9810.0930.1730.99594.1
3.32-3.423.30.11318530.9870.070.1341.01395.1
3.42-3.533.40.09318920.9920.0560.111.1296.4
3.53-3.653.60.0818810.9930.0450.0931.23596.5
3.65-3.83.70.07319670.9950.040.0841.44297.3
3.8-3.973.90.06418860.9950.0340.0731.49997.9
3.97-4.184.10.05519770.9970.0280.0621.51898.9
4.18-4.444.20.0519360.9970.0250.0561.75198.1
4.44-4.784.30.04319400.9970.0220.0491.65197.6
4.78-5.264.50.03819530.9980.0180.0421.37297.4
5.26-6.024.50.03619690.9990.0170.041.17797.7
6.02-7.564.50.03119790.9990.0150.0351.15697
7.56-304.30.02319800.9990.0120.0261.25292.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
HKL-2000data scaling
Cootmodel building
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.79→30 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.887 / WRfactor Rfree: 0.2599 / WRfactor Rwork: 0.1816 / FOM work R set: 0.7579 / SU B: 38.514 / SU ML: 0.327 / SU R Cruickshank DPI: 1.1262 / SU Rfree: 0.3902 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.126 / ESU R Free: 0.39 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2773 1883 5.1 %RANDOM
Rwork0.1981 ---
obs0.2021 35324 93.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 191.68 Å2 / Biso mean: 70.769 Å2 / Biso min: 30.26 Å2
Baniso -1Baniso -2Baniso -3
1-1.66 Å20 Å20 Å2
2---4.08 Å2-0 Å2
3---2.42 Å2
Refinement stepCycle: final / Resolution: 2.79→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8203 0 41 31 8275
Biso mean--60.25 46.96 -
Num. residues----1025
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0198436
X-RAY DIFFRACTIONr_bond_other_d0.0010.028008
X-RAY DIFFRACTIONr_angle_refined_deg1.5481.96311381
X-RAY DIFFRACTIONr_angle_other_deg0.837318446
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.13751027
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.57923.827405
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.174151525
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2771564
X-RAY DIFFRACTIONr_chiral_restr0.0790.21225
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.029536
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021991
X-RAY DIFFRACTIONr_mcbond_it2.4363.8374109
X-RAY DIFFRACTIONr_mcbond_other2.4333.8374107
X-RAY DIFFRACTIONr_mcangle_it4.0965.7445132
LS refinement shellResolution: 2.79→2.862 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.414 102 -
Rwork0.353 2094 -
all-2196 -
obs--76.41 %
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)
10.8361-0.3091-0.35730.7190.84531.0202-0.2127-0.1702-0.20690.0085-0.0440.23680.0711-0.07540.25670.350.06650.14630.18480.02720.3717-44.52893.183131.6993
22.5385-0.3383-0.87951.54560.96981.1688-0.0526-0.35960.0043-0.42240.3212-0.31920.02720.2273-0.26860.4662-0.01590.14530.2024-0.06370.2715-16.18417.352915.4152
31.5031-1.8057-1.11072.32881.57971.29730.1991-0.69940.489-0.37020.7427-0.8365-0.23790.4218-0.94190.178-0.08550.12430.383-0.17140.8733-21.217736.096632.6083
40.7096-0.1046-0.3193.0671-0.28450.18440.01840.06210.0094-0.17-0.0145-0.1483-0.0239-0.0454-0.00380.46050.04180.08110.10560.03620.2448-21.5904-22.337716.1038
50.0939-0.22290.14391.4509-0.13150.4310.0124-0.0196-0.0842-0.2520.05180.24370.00690.089-0.06420.43570.0110.11660.09920.0120.3281-24.5993-56.265626.8809
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A30 - 184
2X-RAY DIFFRACTION1A513 - 547
3X-RAY DIFFRACTION2A185 - 270
4X-RAY DIFFRACTION2A701
5X-RAY DIFFRACTION2A487 - 512
6X-RAY DIFFRACTION3A271 - 475
7X-RAY DIFFRACTION4A548 - 668
8X-RAY DIFFRACTION5B2 - 340
9X-RAY DIFFRACTION5G5 - 62

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