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- PDB-5he1: Human GRK2 in complex with Gbetagamma subunits and CCG224062 -

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Basic information

Entry
Database: PDB / ID: 5he1
TitleHuman GRK2 in complex with Gbetagamma subunits and CCG224062
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


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-ZS2 / 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: 3.15 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
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)120,4955
Polymers119,9213
Non-polymers5742
Water61334
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6820 Å2
ΔGint-49 kcal/mol
Surface area47090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)62.023, 241.364, 212.970
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: 74789.906 Da / Num. of mol.: 1 / Fragment: UNP residues 29-670 / Mutation: S670A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADRBK1, BARK, BARK1, GRK2 / 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: 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

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Non-polymers , 3 types, 36 molecules

#4: Chemical ChemComp-ZS2 / (4~{S})-4-[4-fluoranyl-3-(isoquinolin-1-ylmethylcarbamoyl)phenyl]-~{N}-(1~{H}-indazol-5-yl)-6-methyl-2-oxidanylidene-3,4-dihydro-1~{H}-pyrimidine-5-carboxamide


Mass: 549.555 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H24FN7O3
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 34 / 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: 3.48 Å3/Da / Density % sol: 64.67 %
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: 3.2→30 Å / Num. obs: 27203 / % possible obs: 96.7 % / Redundancy: 7.3 % / Rmerge(I) obs: 0.146 / Rpim(I) all: 0.065 / Rrim(I) all: 0.158 / Χ2: 2.116 / Net I/av σ(I): 17.838 / Net I/σ(I): 8.2 / Num. measured all: 197708
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Num. unique allCC1/2Rpim(I) allΧ2% possible allRmerge(I) obsRrim(I) all
3.2-3.266.912770.7470.5330.93892.3
3.26-3.31713110.7620.5010.97692.5
3.31-3.387.412980.8410.4051.04595.9
3.38-3.457.412840.8440.3481.05993.70.9240.992
3.45-3.527.413250.9070.2811.111940.7510.805
3.52-3.67.413060.9240.2141.26595.10.5690.61
3.6-3.697.413320.9440.1831.31594.60.4850.52
3.69-3.797.413130.950.1541.44597.10.4090.439
3.79-3.97.213540.9680.1261.65695.60.3310.356
3.9-4.037.313460.9720.1031.78596.80.270.29
4.03-4.177.213570.980.092.07596.70.2330.251
4.17-4.347.113560.9860.0722.341980.1840.198
4.34-4.546.913880.9890.0612.66797.80.1520.165
4.54-4.786.913590.9910.0522.85299.10.1280.139
4.78-5.07714030.9920.0483.01699.50.1180.127
5.07-5.467.414270.9930.0483.1161000.120.129
5.46-6.01814130.9940.0472.97599.90.1230.132
6.01-6.87814350.9950.0362.98499.50.0950.102
6.87-8.627.514200.9970.0273.3998.10.0690.074
8.62-306.514990.9970.0213.60997.50.0520.056

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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: 3.15→30 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.922 / WRfactor Rfree: 0.231 / WRfactor Rwork: 0.1479 / FOM work R set: 0.7885 / SU B: 50.515 / SU ML: 0.384 / SU R Cruickshank DPI: 0.3128 / SU Rfree: 0.4597 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.46 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2502 1395 5.1 %RANDOM
Rwork0.1677 ---
obs0.1718 25781 96.07 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 224.95 Å2 / Biso mean: 99.419 Å2 / Biso min: 43.24 Å2
Baniso -1Baniso -2Baniso -3
1-3.08 Å2-0 Å20 Å2
2---5.12 Å20 Å2
3---2.04 Å2
Refinement stepCycle: final / Resolution: 3.15→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8159 0 42 34 8235
Biso mean--113.23 65.71 -
Num. residues----1019
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0198389
X-RAY DIFFRACTIONr_bond_other_d0.0010.027961
X-RAY DIFFRACTIONr_angle_refined_deg1.5721.96211312
X-RAY DIFFRACTIONr_angle_other_deg0.816318332
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.40851018
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.8623.722403
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.054151515
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4191565
X-RAY DIFFRACTIONr_chiral_restr0.080.21213
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.029476
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021993
X-RAY DIFFRACTIONr_mcbond_it5.127.5314081
X-RAY DIFFRACTIONr_mcbond_other5.1197.5294080
X-RAY DIFFRACTIONr_mcangle_it8.06611.2835097
LS refinement shellResolution: 3.15→3.231 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.378 92 -
Rwork0.29 1657 -
all-1749 -
obs--86.03 %
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)
11.08510.279-0.11840.20060.19780.5548-0.1215-0.10360.04850.0303-0.08150.16450.1189-0.00690.2030.38480.05140.26890.0645-0.04550.3221-45.21833.104932.0742
22.44670.1839-0.69691.05120.72220.8394-0.2426-0.07170.0431-0.05440.1991-0.04880.14540.19180.04350.3770.11180.09210.10180.0120.1357-17.188117.205816.0151
30.9863-0.4941-0.02691.35190.71620.5779-0.0721-0.2020.2075-0.01460.267-0.1186-0.00920.1834-0.19490.21340.0379-0.04460.1592-0.15110.2809-21.977836.406232.8558
40.2841-0.002-0.19551.54380.23860.2380.10850.0162-0.093-0.0934-0.065-0.112-0.2052-0.0497-0.04350.4780.1210.15210.03210.04560.1572-22.4648-22.083515.8829
50.2353-0.530.19891.4131-0.17620.5960.08360.0104-0.1022-0.12620.05410.2103-0.00360.1088-0.13770.30810.04120.02510.0604-0.02060.1607-25.5825-56.200626.4478
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A29 - 184
2X-RAY DIFFRACTION1A513 - 545
3X-RAY DIFFRACTION2A185 - 270
4X-RAY DIFFRACTION2A701
5X-RAY DIFFRACTION2A493 - 512
6X-RAY DIFFRACTION3A271 - 473
7X-RAY DIFFRACTION4A549 - 668
8X-RAY DIFFRACTION5B2 - 340
9X-RAY DIFFRACTION5G7 - 68

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