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- PDB-5he3: Bovine GRK2 in complex with Gbetagamma subunits and CCG224411 -

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Basic information

Entry
Database: PDB / ID: 5he3
TitleBovine GRK2 in complex with Gbetagamma subunits and CCG224411
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Beta-adrenergic receptor kinase 1G protein-coupled receptor kinase 2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / RGS / kinase / PH / WD-40 / inhibitor complex / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


Calmodulin induced events / Activation of SMO / beta-adrenergic-receptor kinase / negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / 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 / Activation of SMO / beta-adrenergic-receptor kinase / negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / 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 / desensitization of G protein-coupled receptor signaling pathway / negative regulation of striated muscle contraction / positive regulation of protein localization to cilium / Cargo recognition for clathrin-mediated endocytosis / regulation of the force of heart contraction / G protein-coupled receptor internalization / positive regulation of smoothened signaling pathway / G alpha (s) signalling events / G alpha (q) signalling events / regulation of signal transduction / cardiac muscle contraction / Olfactory Signaling Pathway / Thromboxane signalling through TP receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Activation of the phototransduction cascade / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G protein-coupled acetylcholine receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / Sensory perception of sweet, bitter, and umami (glutamate) taste / ADP signalling through P2Y purinoceptor 12 / viral genome replication / G beta:gamma signalling through BTK / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Vasopressin regulates renal water homeostasis via Aquaporins / photoreceptor disc membrane / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / sensory perception of taste / cellular response to catecholamine stimulus / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / ADORA2B mediated anti-inflammatory cytokines production / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / ADP signalling through P2Y purinoceptor 1 / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / GPER1 signaling / heterotrimeric G-protein complex / cell projection / Inactivation, recovery and regulation of the phototransduction cascade / intracellular protein transport / G alpha (12/13) signalling events / signaling receptor complex adaptor activity / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / presynapse / G protein-coupled receptor binding / retina development in camera-type eye / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / peptidyl-threonine phosphorylation / heart development / cell population proliferation / postsynapse / Ras protein signal transduction / Extra-nuclear estrogen signaling / lysosomal membrane / peptidyl-serine phosphorylation / G protein-coupled receptor signaling pathway / protein kinase activity / GTPase activity / synapse / protein-containing complex binding / viral entry into host cell / protein phosphorylation / 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, subdomain 2 / RGS domain / RGS domain profile. ...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, subdomain 2 / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / RGS domain superfamily / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / YVTN repeat-like/Quinoprotein amine dehydrogenase / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain / 7 Propeller / Methylamine Dehydrogenase; Chain H / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / Few Secondary Structures / Irregular / G-protein beta WD-40 repeat / Helix Hairpins / PH-like domain superfamily / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Roll / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-FF1 / 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 (cattle)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.74 Å
AuthorsCato, M.C. / 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

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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)120,4905
Polymers119,9253
Non-polymers5652
Water70339
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6950 Å2
ΔGint-47 kcal/mol
Surface area45850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.031, 239.412, 208.625
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 74778.086 Da / Num. of mol.: 1 / Fragment: UNP residues 30-670
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: ADRBK1, GRK2 / Plasmid: pFastBacDual / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P21146, beta-adrenergic-receptor kinase

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG

#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: 7861.143 Da / Num. of mol.: 1
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

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Non-polymers , 3 types, 41 molecules

#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-FF1 / (4~{S})-4-[3-[2-(2,6-dimethylphenyl)ethylcarbamoyl]-4-fluoranyl-phenyl]-~{N}-(1~{H}-indazol-5-yl)-6-methyl-2-oxidanylidene-3,4-dihydro-1~{H}-pyrimidine-5-carboxamide


Mass: 540.588 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H29FN6O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 39 / 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: 64.06 %
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 wavelength
IDWavelength (Å)Relative weight
10.97861
20.978571
ReflectionResolution: 2.8→30 Å / Num. obs: 36395 / % possible obs: 93.3 % / Redundancy: 4.6 % / Rmerge(I) obs: 0.104 / Rpim(I) all: 0.053 / Rrim(I) all: 0.114 / Χ2: 1.652 / Net I/av σ(I): 19.607 / Net I/σ(I): 8.1 / Num. measured all: 168944
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allΧ2% possible allRrim(I) all
2.8-2.854.50.93618000.7690.4860.82893.5
2.85-2.94.50.84617680.8060.4340.88892.20.956
2.9-2.964.70.71717710.8270.3620.9192.50.807
2.96-3.024.60.58918050.8730.2970.97693.10.662
3.02-3.084.70.50817720.8850.2530.993930.57
3.08-3.154.70.4117850.9290.2051.04792.90.46
3.15-3.234.70.32317740.9460.1621.11592.50.363
3.23-3.324.70.27817850.9590.1391.22892.20.312
3.32-3.424.70.21717800.970.111.34692.20.245
3.42-3.534.70.18117910.9770.0911.43591.80.203
3.53-3.654.70.15917540.980.0811.76910.179
3.65-3.84.70.13317800.9850.0671.95391.70.149
3.8-3.974.70.11117770.9890.0561.9391.20.125
3.97-4.184.70.08917800.9920.046292.40.101
4.18-4.444.60.0818020.9910.0422.17791.80.09
4.44-4.784.50.07418220.9920.0392.45993.40.084
4.78-5.264.50.06918820.9910.0372.395.40.078
5.26-6.024.80.07119490.9930.0362.22297.40.08
6.02-7.564.80.05919740.9960.032.09198.30.067
7.56-304.30.05120440.9960.0263.17496.80.057

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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: 2.74→30 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.916 / WRfactor Rfree: 0.2411 / WRfactor Rwork: 0.1806 / FOM work R set: 0.7788 / SU B: 34.567 / SU ML: 0.306 / SU R Cruickshank DPI: 1.3489 / SU Rfree: 0.3628 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.349 / ESU R Free: 0.363 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2571 1871 5.1 %RANDOM
Rwork0.195 ---
obs0.1981 34487 90.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 209.52 Å2 / Biso mean: 75.206 Å2 / Biso min: 3.57 Å2
Baniso -1Baniso -2Baniso -3
1-1.65 Å20 Å2-0 Å2
2---5.15 Å2-0 Å2
3---3.5 Å2
Refinement stepCycle: final / Resolution: 2.74→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8166 0 41 39 8246
Biso mean--116.81 40.76 -
Num. residues----1020
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0198399
X-RAY DIFFRACTIONr_bond_other_d0.0010.027993
X-RAY DIFFRACTIONr_angle_refined_deg1.5671.96311331
X-RAY DIFFRACTIONr_angle_other_deg0.793318407
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.14151022
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.34423.756402
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.895151522
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2781565
X-RAY DIFFRACTIONr_chiral_restr0.0760.21221
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.029487
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021985
X-RAY DIFFRACTIONr_mcbond_it2.9394.5014088
X-RAY DIFFRACTIONr_mcbond_other2.9364.5014087
X-RAY DIFFRACTIONr_mcangle_it4.7866.7425108
LS refinement shellResolution: 2.74→2.811 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.381 87 -
Rwork0.339 1582 -
all-1669 -
obs--58.07 %
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)
10.9399-0.3853-0.47820.47860.63071.0323-0.1891-0.1721-0.1552-0.01220.0020.18110.1071-0.05030.18710.30080.02460.1180.18610.00290.238-44.19643.303330.9108
22.2509-0.2238-0.76171.31691.28891.7088-0.1728-0.24020.0428-0.26750.2793-0.11820.04660.328-0.10650.37420.04770.09540.2163-0.02850.0958-16.413816.716815.3445
31.8984-1.8793-1.00622.6551.83571.49750.1599-1.0680.3994-0.59660.9058-1.0207-0.44410.492-1.06560.2801-0.05190.21460.6206-0.19580.8169-20.912935.594231.8764
40.5424-0.292-0.33512.7644-0.21320.28420.05340.01950.0004-0.236-0.024-0.1517-0.065-0.0334-0.02950.41030.05390.13760.07690.0420.1636-21.6216-22.111315.7635
50.1395-0.37360.12511.4166-0.07990.42320.048-0.0406-0.0694-0.24880.03380.16130.00130.0578-0.08180.3321-0.00260.0970.1577-0.00490.146-24.4665-55.785426.1984
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 DIFFRACTION2A493 - 512
5X-RAY DIFFRACTION2A701
6X-RAY DIFFRACTION3A271 - 474
7X-RAY DIFFRACTION4A548 - 668
8X-RAY DIFFRACTION5B2 - 340
9X-RAY DIFFRACTION5G6 - 63

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