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- PDB-5uuu: Design, Synthesis, and Evaluation of the First Selective and Pote... -

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Basic information

Entry
Database: PDB / ID: 5uuu
TitleDesign, Synthesis, and Evaluation of the First Selective and Potent G-protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure
ComponentsBeta-adrenergic receptor kinase 1G protein-coupled receptor kinase 2
KeywordsTransferase/Transferase Inhibitor / Kinase / Inhibitor / Heart Failure / 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 / G protein-coupled acetylcholine receptor signaling pathway / cilium / receptor internalization / Cargo recognition for clathrin-mediated endocytosis / presynapse / heart development / G alpha (s) signalling events / postsynapse / G alpha (q) signalling events / peptidyl-serine phosphorylation / protein kinase activity / symbiont entry into host cell / G protein-coupled receptor signaling pathway / ATP binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
GPCR kinase / Regulator of G protein signaling domain / RGS, subdomain 2 / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / 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, subdomain 2 / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / 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. / Pleckstrin homology domain / PH-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / 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
Similarity search - Domain/homology
Chem-QRW / Beta-adrenergic receptor kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsHoffman, I.D. / Lawson, J.D.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure.
Authors: Okawa, T. / Aramaki, Y. / Yamamoto, M. / Kobayashi, T. / Fukumoto, S. / Toyoda, Y. / Henta, T. / Hata, A. / Ikeda, S. / Kaneko, M. / Hoffman, I.D. / Sang, B.C. / Zou, H. / Kawamoto, T.
History
DepositionFeb 17, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 26, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 6, 2017Group: Database references / Refinement description / Category: citation / software
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Beta-adrenergic receptor kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,0905
Polymers63,2361
Non-polymers8544
Water63135
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)126.180, 126.180, 96.369
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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Components

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


Mass: 63236.098 Da / Num. of mol.: 1 / Fragment: UNP residues 23-538
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRK2, ADRBK1, BARK, BARK1 / Plasmid: pFastBacHTb / Production host: Baculovirus expression vector pFastBac1-HM / Strain (production host): Sf9
References: UniProt: P25098, beta-adrenergic-receptor kinase
#2: Chemical ChemComp-QRW / 3-({[4-methyl-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]methyl}amino)-N-[2-(trifluoromethyl)benzyl]benzamide


Mass: 466.458 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H21F3N6O
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 35 / 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: 3.5 Å3/Da / Density % sol: 64.88 %
Crystal growTemperature: 273 K / Method: vapor diffusion, sitting drop / pH: 5.6
Details: 18% PEG MME 2000, 0.1 M MES pH 5.6, and 0.0175M Ammonium Sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL14-1 / Wavelength: 0.97949 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jul 10, 2014
Details: Flat collimating Rh coated mirror, toroidal focussing mirror
RadiationMonochromator: Si (111) double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 24714 / % possible obs: 100 % / Redundancy: 7.2 % / Rmerge(I) obs: 0.083 / Rpim(I) all: 0.039 / Rrim(I) all: 0.089 / Χ2: 1.002 / Net I/σ(I): 7.1 / Num. measured all: 177721
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)CC1/2Rpim(I) allΧ2% possible allRmerge(I) obsRrim(I) all
2.7-2.757.30.5570.6490.942100
2.75-2.87.30.7160.5450.974100
2.8-2.857.30.6530.490.997100
2.85-2.917.30.750.4180.974100
2.91-2.977.20.8160.3381.011000.8870.952
2.97-3.047.20.8710.2551.0411000.6710.72
3.04-3.127.30.910.2061.031000.5450.584
3.12-3.27.30.9430.1511.0271000.3970.426
3.2-3.37.20.9710.1171.0151000.3070.329
3.3-3.47.20.9760.11.0241000.260.279
3.4-3.527.20.9870.0741.0131000.1930.207
3.52-3.667.30.9920.0560.9951000.1450.156
3.66-3.837.20.9950.0430.9931000.1110.119
3.83-4.037.20.9970.03411000.0870.094
4.03-4.297.20.9970.031.0481000.0770.083
4.29-4.627.20.9980.02311000.0570.062
4.62-5.087.10.9990.0190.9821000.0470.051
5.08-5.817.10.9990.0190.9931000.0470.051
5.81-7.327.10.9990.0160.9781000.040.043
7.32-506.70.9990.010.99799.50.0240.026

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Processing

Software
NameVersionClassification
REFMACrefinement
PDB_EXTRACT3.22data extraction
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→30 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.918 / SU B: 25.695 / SU ML: 0.24 / SU R Cruickshank DPI: 0.3528 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.353 / ESU R Free: 0.272
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.257 1258 5.1 %RANDOM
Rwork0.2128 ---
obs0.2151 23419 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 158.46 Å2 / Biso mean: 77.691 Å2 / Biso min: 42.05 Å2
Baniso -1Baniso -2Baniso -3
1--1.21 Å2-0.61 Å2-0 Å2
2---1.21 Å20 Å2
3---3.93 Å2
Refinement stepCycle: final / Resolution: 2.7→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3355 0 67 35 3457
Biso mean--67 56.44 -
Num. residues----414
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0193516
X-RAY DIFFRACTIONr_bond_other_d0.0010.023326
X-RAY DIFFRACTIONr_angle_refined_deg1.0651.9854739
X-RAY DIFFRACTIONr_angle_other_deg0.81537668
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.95417
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.27323.333168
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.58815634
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.231527
X-RAY DIFFRACTIONr_chiral_restr0.0610.2500
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213899
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02825
LS refinement shellResolution: 2.7→2.77 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.385 95 -
Rwork0.334 1675 -
all-1770 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: -46.0954 Å / Origin y: 32.9099 Å / Origin z: -37.9371 Å
111213212223313233
T0.0728 Å20.0158 Å2-0.0359 Å2-0.114 Å2-0.066 Å2--0.1185 Å2
L0.9272 °20.949 °2-0.4218 °2-4.1958 °2-1.1524 °2--2.4026 °2
S-0.0982 Å °-0.1274 Å °-0.1026 Å °0.2311 Å °0.1247 Å °-0.4833 Å °0.0145 Å °0.0189 Å °-0.0265 Å °

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