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- PDB-7k7z: Structure of a hit for G Protein Coupled Receptor Kinase 2 (GRK2)... -

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Basic information

Entry
Database: PDB / ID: 7k7z
TitleStructure of a hit for G Protein Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure
Components
  • 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
KeywordsSIGNALING PROTEIN / TRANSFERASE/INHIBITOR / serine/threonine protein kinase / 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 / Edg-2 lysophosphatidic acid receptor binding / alpha-2A adrenergic receptor binding / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / tachykinin receptor signaling pathway / negative regulation of striated muscle contraction / positive regulation of catecholamine secretion ...negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / beta-adrenergic-receptor kinase / Edg-2 lysophosphatidic acid receptor binding / alpha-2A adrenergic receptor binding / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / tachykinin receptor signaling pathway / negative regulation of striated muscle contraction / positive regulation of catecholamine secretion / desensitization of G protein-coupled receptor signaling pathway / Activation of SMO / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / 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 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / 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 / GPER1 signaling / Cargo recognition for clathrin-mediated endocytosis / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / presynapse / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / heart development / retina development in camera-type eye / GTPase binding / Ca2+ pathway / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / 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 / lysosomal membrane / GTPase activity / synapse / symbiont entry into host cell / protein-containing complex binding / signal transduction / extracellular exosome / ATP binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
GPCR kinase / Regulator of G protein signaling domain / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / RGS, subdomain 2 / RGS domain superfamily / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. ...GPCR kinase / Regulator of G protein signaling domain / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / RGS, subdomain 2 / RGS domain superfamily / 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. / YVTN repeat-like/Quinoprotein amine dehydrogenase / Pleckstrin homology domain / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / PH-like domain superfamily / WD domain, G-beta repeat / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / Protein kinase domain / WD40-repeat-containing domain superfamily / 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 / Mainly Beta
Similarity search - Domain/homology
3-benzyl-7-(1H-pyrazol-4-yl)quinazolin-4(3H)-one / 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: 2.60608692764 Å
AuthorsSpurlino, J.C. / Milligan, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Hit-to-lead optimization and discovery of a potent, and orally bioavailable G protein coupled receptor kinase 2 (GRK2) inhibitor.
Authors: Xu, G. / Gaul, M.D. / Liu, Z. / DesJarlais, R.L. / Qi, J. / Wang, W. / Krosky, D. / Petrounia, I. / Milligan, C.M. / Hermans, A. / Lu, H.R. / Huang, D.Z. / Xu, J.Z. / Spurlino, J.C.
History
DepositionSep 24, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 28, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)118,6534
Polymers118,3513
Non-polymers3021
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6560 Å2
ΔGint-50 kcal/mol
Surface area46290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)194.679, 70.689, 111.503
Angle α, β, γ (deg.)90.000, 110.460, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y

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Components

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


Mass: 74545.641 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRK2, ADRBK1, BARK, BARK1 / Production host: unidentified baculovirus
References: UniProt: P25098, 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 / Production host: unidentified baculovirus / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 6519.523 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: unidentified baculovirus / References: UniProt: P59768
#4: Chemical ChemComp-W4G / 3-benzyl-7-(1H-pyrazol-4-yl)quinazolin-4(3H)-one


Mass: 302.330 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H14N4O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: 3.04 Å3/Da / Density % sol: 59.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5 / Details: 2% PEG 3350, 0.1M MES pH 6.5, 0.2M NaCl

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Oct 13, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. obs: 43160 / % possible obs: 99.2 % / Redundancy: 3.4 % / Biso Wilson estimate: 52.338872052 Å2 / Rmerge(I) obs: 0.081 / Rpim(I) all: 0.073 / Net I/σ(I): 9.96
Reflection shellResolution: 2.6→2.64 Å / Num. unique obs: 2147 / CC1/2: 0.577

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Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: GRK2

Resolution: 2.60608692764→37.1456237759 Å / SU ML: 0.3874797241 / Cross valid method: THROUGHOUT / σ(F): 1.33786888298 / Phase error: 30.7403996444
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.261883490594 1988 4.61702819453 %
Rwork0.204642341506 41070 -
obs0.207319145272 43058 98.5714939792 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 72.4782885558 Å2
Refinement stepCycle: LAST / Resolution: 2.60608692764→37.1456237759 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8160 0 23 0 8183
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002300615086038378
X-RAY DIFFRACTIONf_angle_d0.52817235237711297
X-RAY DIFFRACTIONf_chiral_restr0.04026541324991213
X-RAY DIFFRACTIONf_plane_restr0.003012968733871478
X-RAY DIFFRACTIONf_dihedral_angle_d13.36947615965072
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6061-2.67120.3796425367841310.3088464498072732X-RAY DIFFRACTION92.8942245295
2.6712-2.74340.3401120112561400.2994779263722898X-RAY DIFFRACTION98.6683988308
2.7434-2.82410.3379482077541400.2992479127262936X-RAY DIFFRACTION98.4635083227
2.8241-2.91530.3684164538261400.27378212112885X-RAY DIFFRACTION98.6305836322
2.9153-3.01940.3788391826981420.276654762032937X-RAY DIFFRACTION98.9395886889
3.0194-3.14020.3343540685131430.2654269595162944X-RAY DIFFRACTION98.8472622478
3.1402-3.28310.2968185002181410.2444562347072925X-RAY DIFFRACTION98.9351403679
3.2831-3.45610.3115318475451440.2316893573332936X-RAY DIFFRACTION99.1309945285
3.4561-3.67240.2856098491561420.2151260788312958X-RAY DIFFRACTION99.104859335
3.6724-3.95570.250841196761430.1918144371832930X-RAY DIFFRACTION99.2571059432
3.9557-4.35320.2603201055441440.1725914679762971X-RAY DIFFRACTION99.3620414673
4.3532-4.98180.1902656314841440.1577038224592973X-RAY DIFFRACTION99.4893073731
4.9818-6.27170.2537077952581460.1930965300473001X-RAY DIFFRACTION99.4627054362
6.2717-37.1440.1895192262211480.1574004885913044X-RAY DIFFRACTION98.8847583643
Refinement TLS params.Method: refined / Origin x: -9.87793689179 Å / Origin y: 13.7000030771 Å / Origin z: 29.03458561 Å
111213212223313233
T0.393459020402 Å20.00257109686944 Å2-0.0276642037721 Å2-0.319144869901 Å2-0.0294874432779 Å2--0.356168860311 Å2
L0.583330258327 °2-0.20097275471 °20.706326175375 °2-0.474732029453 °2-0.53583572711 °2--2.06536813644 °2
S0.196562180134 Å °-0.0489905511632 Å °-0.139311157308 Å °0.0215175371606 Å °-0.0159972007522 Å °0.0163900680499 Å °0.385851971321 Å °0.107855449429 Å °-0.156146145621 Å °
Refinement TLS groupSelection details: all

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