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- PDB-5ukk: Human GRK2 in complex with human G-beta-gamma subunits and CCG211... -

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Basic information

Entry
Database: PDB / ID: 5ukk
TitleHuman GRK2 in complex with human G-beta-gamma subunits and CCG211998 (14ak)
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Beta-adrenergic receptor kinase 1G protein-coupled receptor kinase 2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / inhibitor complex / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


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 / positive regulation of catecholamine secretion / tachykinin receptor signaling pathway / 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 / positive regulation of catecholamine secretion / tachykinin receptor signaling pathway / Activation of SMO / negative regulation of striated muscle contraction / desensitization of G protein-coupled receptor signaling pathway / regulation of the force of heart contraction / Calmodulin induced events / cardiac muscle contraction / viral genome replication / 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 activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / cilium / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / receptor internalization / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / Cargo recognition for clathrin-mediated endocytosis / presynapse / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / heart development / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / postsynapse / G alpha (q) signalling events / peptidyl-serine phosphorylation / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / protein kinase activity / symbiont entry into host cell / G protein-coupled receptor signaling pathway / 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, 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. / 7 Propeller / Methylamine Dehydrogenase; Chain H / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / 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 / Few Secondary Structures / Irregular / Helix Hairpins / PH-like domain superfamily / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Roll / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / WD40/YVTN repeat-like-containing domain superfamily / 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-8DJ / 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: 2.6 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 / Category: pdbx_audit_support / 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)118,9215
Polymers118,4333
Non-polymers4882
Water77543
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6410 Å2
ΔGint-50 kcal/mol
Surface area47070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)113.123, 62.423, 102.035
Angle α, β, γ (deg.)90.000, 92.810, 90.000
Int Tables number3
Space group name H-MP121

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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: 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: pFastBac / 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: 6347.342 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, 45 molecules

#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-8DJ / 5-[(3S,4R)-3-{[(2H-1,3-benzodioxol-5-yl)oxy]methyl}piperidin-4-yl]-2-fluoro-N-[(pyridin-2-yl)methyl]benzamide


Mass: 463.501 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H26FN3O4
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 43 / 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: 3.12 Å3/Da / Density % sol: 60.6 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 50 mM MES, 8-16% PEG3350, 0.8-1.2 M sodium chloride

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97849 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 12, 2013
RadiationMonochromator: diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97849 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 39963 / % possible obs: 92.7 % / Redundancy: 2.6 % / Rmerge(I) obs: 0.098 / Net I/σ(I): 9.24
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
2.6-2.642.50.8490.83194.3
2.64-2.692.50.725194.5
2.69-2.742.50.676194.3
2.74-2.82.60.568194.1
2.8-2.862.60.482194.6
2.86-2.932.60.375193.9
2.93-32.60.329193.7
3-3.082.60.284194.1
3.08-3.172.60.238194.1
3.17-3.282.60.19194.1
3.28-3.392.60.153193.1
3.39-3.532.60.134193.4
3.53-3.692.60.114193
3.69-3.882.60.096192.4
3.88-4.132.60.085192.5
4.13-4.452.60.075192
4.45-4.892.60.076191.3
4.89-5.62.60.067190.7
5.6-7.052.70.058189.5
7.05-502.60.038185.7

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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: 2.6→30 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.911 / SU B: 39.783 / SU ML: 0.36 / SU R Cruickshank DPI: 0.9635 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.963 / ESU R Free: 0.372 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2807 1912 5 %RANDOM
Rwork0.2207 ---
obs0.2237 35989 85.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 194.75 Å2 / Biso mean: 79.624 Å2 / Biso min: 31.95 Å2
Baniso -1Baniso -2Baniso -3
1--2.7 Å20 Å20.83 Å2
2---0.29 Å20 Å2
3---2.89 Å2
Refinement stepCycle: final / Resolution: 2.6→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8077 0 35 43 8155
Biso mean--70.35 54.92 -
Num. residues----1009
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0198295
X-RAY DIFFRACTIONr_bond_other_d0.0020.027862
X-RAY DIFFRACTIONr_angle_refined_deg1.5311.95911183
X-RAY DIFFRACTIONr_angle_other_deg0.978318097
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.33351008
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.41223.753405
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.079151492
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.9721566
X-RAY DIFFRACTIONr_chiral_restr0.080.21199
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.029384
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021972
LS refinement shellResolution: 2.6→2.667 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.336 88 -
Rwork0.336 1705 -
all-1793 -
obs--56.53 %
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)
10.4060.21940.53570.6847-0.00270.86020.0610.3174-0.06420.10730.05430.04790.06090.4592-0.11530.3257-0.0350.02320.4903-0.19630.0996149.720623.96366.1329
21.6911-0.20630.37041.29980.75720.862-0.05380.0884-0.1839-0.0213-0.04970.09-0.1267-0.13420.10350.3626-0.03260.02060.2401-0.10630.0761115.911128.398269.833
31.1020.10720.54620.4275-0.181.5077-0.1394-0.05020.0930.02760.1360.0918-0.21560.04940.00350.5175-0.00370.00640.1776-0.02640.0474122.582750.154278.0654
40.8199-0.5427-0.51350.56230.76321.88160.09570.0020.04790.01230.02290.03340.29790.0714-0.11850.35690.027-0.05480.2446-0.10970.1485129.37874.005943.0859
50.51780.2176-0.0730.30020.43442.0774-0.0992-0.01170.1006-0.01640.12330.03360.31560.2764-0.02410.4590.1216-0.05230.2557-0.07580.0463147.4086-8.479115.4201
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 DIFFRACTION2A501 - 512
5X-RAY DIFFRACTION3A271 - 484
6X-RAY DIFFRACTION4A548 - 667
7X-RAY DIFFRACTION5B2 - 340
8X-RAY DIFFRACTION5G8 - 64
9X-RAY DIFFRACTION2A702

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