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- PDB-7k7l: Structure of a hit for G Protein Coupled Receptor Kinase 2 (GRK2)... -

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Basic information

Entry
Database: PDB / ID: 7k7l
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 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / 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 / presynapse / sensory perception of taste / 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 / cytosol / cytoplasm
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-6-(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: 2.539 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 23, 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: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_residues
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

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)118,6785
Polymers118,3513
Non-polymers3272
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6560 Å2
ΔGint-49 kcal/mol
Surface area45950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)194.398, 70.766, 111.236
Angle α, β, γ (deg.)90.000, 110.580, 90.000
Int Tables number5
Space group name H-MC121

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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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-W4D / 3-benzyl-6-(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: 3.03 Å3/Da / Density % sol: 59.35 %
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: Dec 15, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.539→50 Å / Num. obs: 43227 / % possible obs: 91.9 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.059 / Rpim(I) all: 0.046 / Rrim(I) all: 0.089 / Net I/σ(I): 16.5
Reflection shellResolution: 2.54→2.63 Å / Num. unique obs: 2465 / CC1/2: 0.884 / CC star: 0.969 / Rpim(I) all: 0.251 / Rrim(I) all: 0.45

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Processing

Software
NameVersionClassification
PHENIXdev_1838refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: GRK2

Resolution: 2.539→33.502 Å / SU ML: 0.36 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 30.57 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2436 1997 4.63 %
Rwork0.2008 41157 -
obs0.2027 43154 91.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 203.55 Å2 / Biso mean: 71.2083 Å2 / Biso min: 19.56 Å2
Refinement stepCycle: final / Resolution: 2.539→33.502 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8102 0 37 0 8139
Biso mean--92.5 --
Num. residues----1012
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.028317
X-RAY DIFFRACTIONf_angle_d0.57511198
X-RAY DIFFRACTIONf_chiral_restr0.0221203
X-RAY DIFFRACTIONf_plane_restr0.0021462
X-RAY DIFFRACTIONf_dihedral_angle_d11.7023127
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.539-2.60240.4024750.3253153849
2.6024-2.67280.36271020.3011211367
2.6728-2.75140.35741250.2851256480
2.7514-2.84020.36261410.2817293792
2.8402-2.94160.32861510.2704313298
2.9416-3.05930.30881550.26843183100
3.0593-3.19840.32011550.26933194100
3.1984-3.36690.30681550.24223194100
3.3669-3.57770.24831550.22463178100
3.5777-3.85350.22761550.19533184100
3.8535-4.24060.20341550.17213209100
4.2406-4.85270.1811560.14573213100
4.8527-6.10780.21481570.17643227100
6.1078-33.5020.21321600.1641329199
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)
11.6110.1675-0.81091.32121.04385.31060.2121-0.35190.23210.0297-0.07980.1863-0.405-0.244-0.07380.46980.0020.01190.3922-0.01910.4105-7.005519.864858.0931
20.8269-0.45650.46661.08-1.0343.74960.28620.1039-0.4013-0.2778-0.16920.0451.24480.1571-0.06650.90820.0827-0.20620.5329-0.05720.61175.6295-11.701857.5667
31.08660.2875-0.13060.8335-0.50031.73510.16350.0232-0.1501-0.3899-0.03950.07660.27190.5839-0.14010.56230.1303-0.07060.5634-0.03960.42719.32534.971147.5723
42.746-0.09481.0222.6505-0.38754.18910.09960.1396-0.26150.02780.055-0.1220.52480.4089-0.13520.38640.0810.02130.3799-0.00580.3058-6.14213.928916.2408
50.9919-0.47171.1931.29060.29952.14510.23760.1337-0.2134-0.1476-0.1690.49160.2802-0.3543-0.02130.40570.0121-0.0610.45350.02060.5294-45.656727.9082-13.1795
61.8971-0.19430.29231.7868-0.77632.2788-0.004-0.31270.13010.1666-0.02580.0896-0.1766-0.03320.04850.24230.04210.04780.2796-0.01740.2951-17.645735.95227.8822
72.73590.2530.60220.6378-0.39323.25830.137-0.05460.0342-0.0197-0.04330.14750.0812-0.1842-0.08020.24080.02190.03680.19390.02920.3391-29.779130.7119-5.375
82.21381.2896-1.76073.3278-3.17296.6580.0975-0.5330.43560.57350.230.4199-0.5583-0.4678-0.38930.34760.05460.06550.49970.09630.6448-53.589431.10070.5368
91.87550.93062.18582.90670.24442.8366-0.06330.65230.7513-0.2256-0.04540.1895-0.71940.13110.12310.48330.06990.02720.44180.1320.4588-30.462442.3964-19.8355
101.5379-1.2003-1.34873.3646-2.59866.69420.36550.43440.7737-0.3797-0.3324-0.5682-0.94980.5429-0.11580.7848-0.03460.20030.57310.17990.6636-8.003644.9695-15.8397
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 30 through 157 )A30 - 157
2X-RAY DIFFRACTION2chain 'A' and (resid 158 through 453 )A158 - 453
3X-RAY DIFFRACTION3chain 'A' and (resid 454 through 547 )A454 - 547
4X-RAY DIFFRACTION4chain 'A' and (resid 548 through 668 )A548 - 668
5X-RAY DIFFRACTION5chain 'B' and (resid 2 through 45 )B2 - 45
6X-RAY DIFFRACTION6chain 'B' and (resid 46 through 161 )B46 - 161
7X-RAY DIFFRACTION7chain 'B' and (resid 162 through 340 )B162 - 340
8X-RAY DIFFRACTION8chain 'G' and (resid 8 through 29 )G8 - 29
9X-RAY DIFFRACTION9chain 'G' and (resid 30 through 52 )G30 - 52
10X-RAY DIFFRACTION10chain 'G' and (resid 53 through 64 )G53 - 64

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