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- PDB-5ukl: Human GRK2 in complex with Gbetagamma subunits and CCG222886 (14bd) -

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Basic information

Entry
Database: PDB / ID: 5ukl
TitleHuman GRK2 in complex with Gbetagamma subunits and CCG222886 (14bd)
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Beta-adrenergic receptor kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / inhibitor complex / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / beta-adrenergic-receptor kinase / 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 / positive regulation of catecholamine secretion / negative regulation of striated muscle contraction ...negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / beta-adrenergic-receptor kinase / 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 / positive regulation of catecholamine secretion / negative regulation of striated muscle contraction / Activation of SMO / desensitization of G protein-coupled receptor signaling pathway / cytoplasmic side of mitochondrial outer membrane / regulation of the force of heart contraction / Calmodulin induced events / cardiac muscle contraction / viral genome replication / G protein-coupled receptor binding / receptor internalization / 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 / Cargo recognition for clathrin-mediated endocytosis / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / presynapse / peptidyl-serine phosphorylation / Thrombin signalling through proteinase activated receptors (PARs) / heart development / GTPase binding / retina development in camera-type eye / Ca2+ pathway / 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 / protein kinase activity / postsynapse / cilium / 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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / 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-SIX / 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 speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsCato, M.C. / Homan, K.T. / Tesmer, J.J.G.
Funding support United States, 12items
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
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL122416 United States
American Heart AssociationN014938 United States
American Heart Association15PRE22730028 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R37 HL061690 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)P01 HL075443 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)P01 HL108806 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)P01 HL091799 United States
Center for Discovery of New Medicine, University of Michigan United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5T32GM008597 United States
Michigan Economic Development Corporation and Michigan Technology Tri-Corridor Grant085P1000817 United States
CitationJournal: J. Med. Chem. / Year: 2017
Title: Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine.
Authors: Waldschmidt, H.V. / Homan, K.T. / Cato, M.C. / Cruz-Rodriguez, O. / Cannavo, A. / Wilson, M.W. / Song, J. / Cheung, J.Y. / Koch, W.J. / Tesmer, J.J. / Larsen, S.D.
History
DepositionJan 23, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 5, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2017Group: Database references
Revision 1.2Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Sep 27, 2017Group: Data collection / Refinement description / Category: diffrn_detector / software / Item: _diffrn_detector.detector
Revision 1.4Dec 4, 2019Group: Author supporting evidence / Derived calculations / Category: pdbx_audit_support / pdbx_struct_special_symmetry / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)119,5365
Polymers119,0313
Non-polymers5052
Water6,990388
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7090 Å2
ΔGint-50 kcal/mol
Surface area47220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)194.255, 71.429, 111.259
Angle α, β, γ (deg.)90.000, 110.510, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-801-

HOH

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 74799.953 Da / Num. of mol.: 1 / Mutation: S670A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRK2, ADRBK1, BARK, BARK1 / Plasmid: pFastBacDual / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P25098, 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: 6945.089 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, 390 molecules

#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-SIX / 2-{5-[(3S,4R)-3-{[(2H-1,3-benzodioxol-5-yl)oxy]methyl}piperidin-4-yl]-2-fluorophenyl}-N-[2-(1H-pyrazol-4-yl)ethyl]acetamide


Mass: 480.531 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H29FN4O4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 388 / 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: 3.07 Å3/Da / Density % sol: 59.94 %
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: 0.97856 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 28, 2014
RadiationMonochromator: diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. obs: 77337 / % possible obs: 100 % / Redundancy: 18.3 % / Rmerge(I) obs: 0.161 / Net I/σ(I): 24.9
Reflection shell
Resolution (Å)Redundancy (%)CC1/2Diffraction-ID% possible allRmerge(I) obs
2.15-2.1911.20.7571100
2.19-2.2313.80.8341100
2.23-2.2715.50.881100
2.27-2.3216.60.9051100
2.32-2.3717.20.9371100
2.37-2.4217.70.951100
2.42-2.4818.20.95611000.962
2.48-2.5518.80.97111000.872
2.55-2.6219.50.97811000.817
2.62-2.71200.98311000.702
2.71-2.8120.20.98711000.554
2.81-2.9220.20.99111000.422
2.92-3.0520.20.99311000.331
3.05-3.2120.20.99511000.245
3.21-3.4120.20.99611000.18
3.41-3.68200.99611000.145
3.68-4.0519.50.99711000.122
4.05-4.6318.80.99711000.103
4.63-5.8319.10.99811000.084
5.83-5018.80.997199.80.078

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMAC5.8.0151refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3V5W

3v5w


Resolution: 2.15→30 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.94 / SU B: 11.331 / SU ML: 0.142 / SU R Cruickshank DPI: 0.1894 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.189 / ESU R Free: 0.172 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2275 3884 5 %RANDOM
Rwork0.1821 ---
obs0.1844 73370 99.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 160.3 Å2 / Biso mean: 55.457 Å2 / Biso min: 22.11 Å2
Baniso -1Baniso -2Baniso -3
1--0.23 Å20 Å2-0.19 Å2
2---0.53 Å2-0 Å2
3---0.7 Å2
Refinement stepCycle: final / Resolution: 2.15→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8249 0 36 388 8673
Biso mean--69.5 46.51 -
Num. residues----1031
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0198475
X-RAY DIFFRACTIONr_bond_other_d0.0020.028043
X-RAY DIFFRACTIONr_angle_refined_deg1.9021.96111429
X-RAY DIFFRACTIONr_angle_other_deg1.069318521
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0951031
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.49323.723411
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.83151522
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6741567
X-RAY DIFFRACTIONr_chiral_restr0.1120.21226
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.029580
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022009
LS refinement shellResolution: 2.149→2.205 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.312 227 -
Rwork0.299 4753 -
all-4980 -
obs--87.41 %
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)
10.369-0.07210.12730.03080.06591.14910.0786-0.03920.12-0.02040.0151-0.00410.06220.0658-0.09370.21230.00520.04260.23450.00350.1689-3.909634.612652.3807
20.9468-0.45461.27010.2499-0.59781.79510.60920.4501-0.2804-0.2338-0.17070.16610.86660.7309-0.43860.53920.4393-0.15950.4479-0.19780.18511.06815.426743.0468
30.5277-0.12441.05680.047-0.30542.37880.50170.0536-0.1482-0.1354-0.00090.10880.94220.1628-0.50080.63220.0423-0.25750.0662-0.03650.3585.6372-1.974966.3362
40.6307-0.24840.80220.1564-0.42641.58390.09620.06110.0814-0.0291-0.02880.05640.38210.2685-0.06740.26560.08540.01960.29890.01520.1453-5.98328.052314.9447
50.6324-0.15790.24390.3022-0.3030.44090.0258-0.04310.0423-0.01490.01610.04370.02250.0011-0.04190.17360.01650.060.23380.02130.1748-28.422348.2207-3.21
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A31 - 184
2X-RAY DIFFRACTION1A513 - 547
3X-RAY DIFFRACTION2A185 - 270
4X-RAY DIFFRACTION2A496 - 512
5X-RAY DIFFRACTION2A702
6X-RAY DIFFRACTION3A271 - 484
7X-RAY DIFFRACTION4A548 - 671
8X-RAY DIFFRACTION5B2 - 340
9X-RAY DIFFRACTION5G8 - 69

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