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- PDB-5he0: Bovine GRK2 in complex with Gbetagamma subunits and CCG215022 -

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Basic information

Entry
Database: PDB / ID: 5he0
TitleBovine GRK2 in complex with Gbetagamma subunits and CCG215022
Components
  • Beta-adrenergic receptor kinase 1G protein-coupled receptor kinase 2
  • 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 / 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 / cardiac muscle contraction / regulation of signal transduction / 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon signaling in metabolic regulation / ADP signalling through P2Y purinoceptor 12 / 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) / viral genome replication / 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 / 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 / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / cell projection / intracellular protein transport / signaling receptor complex adaptor activity / extracellular vesicle / ADORA2B mediated anti-inflammatory cytokines production / Thrombin signalling through proteinase activated receptors (PARs) / phospholipase C-activating G protein-coupled receptor signaling pathway / presynapse / GTPase binding / Ca2+ pathway / 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 / postsynapse / cell population proliferation / heart development / Ras protein signal transduction / Extra-nuclear estrogen signaling / lysosomal membrane / G protein-coupled receptor signaling pathway / peptidyl-serine phosphorylation / 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. / 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 circular profile. / Trp-Asp (WD) repeats signature. / 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 / Protein kinase domain / Phosphorylase Kinase; domain 1 / 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-453 / 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: 2.56 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 Grant85P1000817 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)120,4084
Polymers119,9093
Non-polymers4991
Water64936
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6720 Å2
ΔGint-49 kcal/mol
Surface area45970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.554, 239.927, 208.872
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 / G protein-coupled receptor kinase 2 / 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 (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: 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
#4: Chemical ChemComp-453 / (4S)-4-{4-fluoro-3-[(pyridin-2-ylmethyl)carbamoyl]phenyl}-N-(1H-indazol-5-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide


Mass: 499.496 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H22FN7O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 36 / 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: 3.47 Å3/Da / Density % sol: 64.51 %
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: 2.6→30 Å / Num. obs: 47002 / % possible obs: 97 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.04 / Rrim(I) all: 0.078 / Χ2: 1.587 / Net I/av σ(I): 25.828 / Net I/σ(I): 12.6 / Num. measured all: 162451
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.6-2.642.50.39120680.9090.2680.4760.89286.1
2.64-2.692.60.39521370.9150.2710.4810.89689.5
2.69-2.742.80.37522540.9180.2480.4510.89293.9
2.74-2.83.10.3622520.9530.2290.4290.90195.7
2.8-2.863.30.34223340.9510.2070.4020.9397.6
2.86-2.933.50.31623250.9650.1830.3660.96497.2
2.93-33.60.27423640.9760.1550.3161.00598.4
3-3.083.70.23723690.9760.1320.2721.05498.8
3.08-3.173.80.19523940.9840.1090.2241.23398.8
3.17-3.283.70.14923570.9880.0850.1721.36499.5
3.28-3.393.80.12424100.9910.0710.1441.55499.4
3.39-3.533.70.10123930.9920.0590.1181.69299.3
3.53-3.693.60.08923820.9920.0530.1052.12299
3.69-3.883.60.07324100.9940.0430.0852.14299.3
3.88-4.123.70.06323900.9940.0370.0742.29399
4.12-4.443.60.05624130.9940.0340.0662.51898.6
4.44-4.893.60.0523840.9950.030.0592.72398.1
4.89-5.593.60.04524380.9970.0260.0522.29898.3
5.59-7.033.60.03624340.9980.0210.0411.67998.4
7.03-303.40.02324940.9990.0150.0281.37695.1

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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
Starting model: 4PNK

4pnk


Resolution: 2.56→30 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.91 / WRfactor Rfree: 0.2609 / WRfactor Rwork: 0.2007 / FOM work R set: 0.7682 / SU B: 27.119 / SU ML: 0.261 / SU R Cruickshank DPI: 0.4502 / SU Rfree: 0.3011 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.45 / ESU R Free: 0.301 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.264 2316 4.9 %RANDOM
Rwork0.2017 ---
obs0.2048 44643 94.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 163.33 Å2 / Biso mean: 71.102 Å2 / Biso min: 37.24 Å2
Baniso -1Baniso -2Baniso -3
1-1.3 Å20 Å2-0 Å2
2---3.76 Å20 Å2
3---2.46 Å2
Refinement stepCycle: final / Resolution: 2.56→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8163 0 37 36 8236
Biso mean--66.02 48.45 -
Num. residues----1020
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0198387
X-RAY DIFFRACTIONr_bond_other_d0.0010.027980
X-RAY DIFFRACTIONr_angle_refined_deg1.6461.96311311
X-RAY DIFFRACTIONr_angle_other_deg0.83318379
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.18451020
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.9323.791401
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.732151521
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.9791564
X-RAY DIFFRACTIONr_chiral_restr0.0820.21218
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.029473
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021981
X-RAY DIFFRACTIONr_mcbond_it3.534.8414086
X-RAY DIFFRACTIONr_mcbond_other3.5294.8414085
X-RAY DIFFRACTIONr_mcangle_it5.5417.2515105
LS refinement shellResolution: 2.56→2.626 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.392 109 -
Rwork0.314 1972 -
all-2081 -
obs--57.53 %
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)
10.7771-0.381-0.32280.85811.00271.2361-0.1987-0.1378-0.18240.0092-0.12080.25730.0694-0.16770.31950.30570.07190.14610.0769-0.0170.2333-44.47613.166231.0748
21.9134-0.2533-0.80621.26521.10891.2518-0.1285-0.2932-0.0164-0.29060.2411-0.1417-0.03560.3211-0.11260.41580.03110.11720.0901-0.01630.1332-16.83716.695115.5035
31.4108-0.8752-0.16331.118-0.00090.52540.0452-0.53710.2091-0.30240.3132-0.0502-0.14090.2778-0.35840.2321-0.08060.08760.2996-0.22130.2503-21.497536.041731.6129
40.6738-0.2241-0.1422.6779-0.31960.09010.0610.1037-0.0127-0.1549-0.056-0.1803-0.0375-0.0281-0.0050.42440.04470.1290.02650.03590.1415-21.7898-22.171415.7557
50.1153-0.29990.14071.4079-0.10950.36240.0368-0.0238-0.0663-0.27950.08010.14260.01180.0317-0.11690.39170.00580.08640.0384-0.00240.1324-24.8465-55.863726.1262
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 DIFFRACTION2A494 - 512
6X-RAY DIFFRACTION3A271 - 475
7X-RAY DIFFRACTION4A548 - 668
8X-RAY DIFFRACTION5B2 - 340
9X-RAY DIFFRACTION5G5 - 64

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