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- PDB-5u7r: Identification of A New Class of Potent Cdc7 Inhibitors Designed ... -

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Basic information

Entry
Database: PDB / ID: 5u7r
TitleIdentification of A New Class of Potent Cdc7 Inhibitors Designed by Putative Pharmacophore Model: Synthesis and Biological Evaluation of 2,3-Dihydrothieno[3,2-d]pyrimidin-4(1H)-ones
ComponentsRho-associated protein kinase 2
KeywordsTRANSFERASE / Serine/threonine kinase / apo-protein
Function / homology
Function and homology information


cellular response to acetylcholine / positive regulation of connective tissue growth factor production / positive regulation of amyloid precursor protein catabolic process / positive regulation of centrosome duplication / regulation of angiotensin-activated signaling pathway / Rho-dependent protein serine/threonine kinase activity / negative regulation of protein localization to lysosome / regulation of keratinocyte differentiation / positive regulation of connective tissue replacement / positive regulation of fibroblast growth factor production ...cellular response to acetylcholine / positive regulation of connective tissue growth factor production / positive regulation of amyloid precursor protein catabolic process / positive regulation of centrosome duplication / regulation of angiotensin-activated signaling pathway / Rho-dependent protein serine/threonine kinase activity / negative regulation of protein localization to lysosome / regulation of keratinocyte differentiation / positive regulation of connective tissue replacement / positive regulation of fibroblast growth factor production / positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process / response to transforming growth factor beta / negative regulation of myosin-light-chain-phosphatase activity / regulation of nervous system process / regulation of cell junction assembly / negative regulation of bicellular tight junction assembly / regulation of protein metabolic process / modulation by host of viral process / regulation of cellular response to hypoxia / positive regulation of protein localization to early endosome / embryonic morphogenesis / negative regulation of nitric oxide biosynthetic process / negative regulation of biomineral tissue development / cellular response to testosterone stimulus / actomyosin structure organization / regulation of establishment of endothelial barrier / RHO GTPases Activate ROCKs / regulation of stress fiber assembly / regulation of cell motility / Sema4D induced cell migration and growth-cone collapse / aortic valve morphogenesis / response to angiotensin / regulation of establishment of cell polarity / RHOBTB1 GTPase cycle / cortical actin cytoskeleton organization / regulation of focal adhesion assembly / RHOB GTPase cycle / positive regulation of amyloid-beta formation / tau-protein kinase activity / EPHA-mediated growth cone collapse / mRNA destabilization / positive regulation of cardiac muscle hypertrophy / RHOC GTPase cycle / RHOH GTPase cycle / centrosome duplication / mitotic cytokinesis / Rho protein signal transduction / smooth muscle contraction / RHOA GTPase cycle / epithelial to mesenchymal transition / canonical NF-kappaB signal transduction / regulation of cell adhesion / positive regulation of stress fiber assembly / EPHB-mediated forward signaling / blood vessel diameter maintenance / negative regulation of angiogenesis / positive regulation of endothelial cell migration / response to ischemia / protein localization to plasma membrane / regulation of actin cytoskeleton organization / peptidyl-threonine phosphorylation / tau protein binding / regulation of circadian rhythm / cytoplasmic ribonucleoprotein granule / small GTPase binding / VEGFA-VEGFR2 Pathway / rhythmic process / G alpha (12/13) signalling events / actin cytoskeleton organization / peptidyl-serine phosphorylation / Potential therapeutics for SARS / positive regulation of MAPK cascade / cytoskeleton / non-specific serine/threonine protein kinase / positive regulation of cell migration / positive regulation of protein phosphorylation / negative regulation of gene expression / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / positive regulation of gene expression / structural molecule activity / RNA binding / ATP binding / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / Rho-associated protein kinase 2, HR1 domain / ROCK, Rho binding domain / Rho-associated protein kinase 1/2 / Rho Binding / Rho-binding (RhoBD) domain profile. / HR1 rho-binding domain / REM-1 domain profile. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) ...: / Rho-associated protein kinase 2, HR1 domain / ROCK, Rho binding domain / Rho-associated protein kinase 1/2 / Rho Binding / Rho-binding (RhoBD) domain profile. / HR1 rho-binding domain / REM-1 domain profile. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PH-like 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. / 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 Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-81G / Rho-associated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.33 Å
AuthorsHoffman, I.D. / Skene, R.J.
CitationJournal: Bioorg. Med. Chem. / Year: 2017
Title: Identification of a new class of potent Cdc7 inhibitors designed by putative pharmacophore model: Synthesis and biological evaluation of 2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-ones.
Authors: Kurasawa, O. / Oguro, Y. / Miyazaki, T. / Homma, M. / Mori, K. / Iwai, K. / Hara, H. / Skene, R. / Hoffman, I. / Ohashi, A. / Yoshida, S. / Ishikawa, T. / Cho, N.
History
DepositionDec 12, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 29, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2017Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software / Item: _software.classification / _software.name
Revision 1.3Mar 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

Downloads & links

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Assembly

Deposited unit
A: Rho-associated protein kinase 2
B: Rho-associated protein kinase 2
C: Rho-associated protein kinase 2
D: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)183,3178
Polymers181,6674
Non-polymers1,6504
Water72140
1
A: Rho-associated protein kinase 2
D: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,6584
Polymers90,8332
Non-polymers8252
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3650 Å2
ΔGint-26 kcal/mol
Surface area34940 Å2
MethodPISA
2
B: Rho-associated protein kinase 2
C: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,6584
Polymers90,8332
Non-polymers8252
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3700 Å2
ΔGint-25 kcal/mol
Surface area35210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.201, 146.137, 110.901
Angle α, β, γ (deg.)90.000, 96.030, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Rho-associated protein kinase 2 / Rho kinase 2 / Rho-associated / coiled-coil-containing protein kinase 2 / coiled-coil-containing ...Rho kinase 2 / Rho-associated / coiled-coil-containing protein kinase 2 / coiled-coil-containing protein kinase II / ROCK-II / p164 ROCK-2


Mass: 45416.645 Da / Num. of mol.: 4 / Fragment: UNP residues 23-417
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ROCK2, KIAA0619 / Production host: unidentified baculovirus
References: UniProt: O75116, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-81G / (1s,4s)-4-(4-fluorophenyl)-4-hydroxy-6'-(5-methyl-1H-pyrazol-4-yl)-1'H-spiro[cyclohexane-1,2'-thieno[3,2-d]pyrimidin]-4'(3'H)-one


Mass: 412.480 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H21FN4O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 40 / 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: 4.07 Å3/Da / Density % sol: 69.77 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.8M Citrate, 0.1M Citrate pH 5.1 in hanging drops at 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.987 Å
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Mar 4, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 3.33→50 Å / Num. obs: 41740 / % possible obs: 100 % / Redundancy: 4.2 % / Rmerge(I) obs: 0.099 / Χ2: 1.001 / Net I/σ(I): 7 / Num. measured all: 173425
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
3.33-3.3940.879199.6
3.39-3.454.10.827199.9
3.45-3.524.20.7121100
3.52-3.594.20.551100
3.59-3.674.20.4361100
3.67-3.754.20.3641100
3.75-3.844.20.31100
3.84-3.954.20.2581100
3.95-4.064.20.2081100
4.06-4.24.20.1761100
4.2-4.344.20.1511100
4.34-4.524.20.1231100
4.52-4.724.20.1161100
4.72-4.974.20.1181100
4.97-5.284.20.1011100
5.28-5.694.10.0971100
5.69-6.2640.0851100
6.26-7.1740.061100
7.17-9.024.20.0371100
9.02-504.10.0281100

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.7.0025refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
PHASERphasing
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.33→49.4 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.937 / SU B: 51.128 / SU ML: 0.357 / SU R Cruickshank DPI: 0.3856 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.462 / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2406 2100 5 %RANDOM
Rwork0.2001 ---
obs0.2021 39569 99.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 249.87 Å2 / Biso mean: 129.871 Å2 / Biso min: 73.4 Å2
Baniso -1Baniso -2Baniso -3
1-6.36 Å20 Å25.47 Å2
2---4.61 Å20 Å2
3----0.6 Å2
Refinement stepCycle: final / Resolution: 3.33→49.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12524 0 116 40 12680
Biso mean--127.86 117.78 -
Num. residues----1543
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.01912965
X-RAY DIFFRACTIONr_angle_refined_deg1.0111.96517542
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.40751533
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.27624.019642
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.272152240
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1081580
X-RAY DIFFRACTIONr_chiral_restr0.0740.21838
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0219968
LS refinement shellResolution: 3.332→3.418 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.386 159 -
Rwork0.36 2765 -
all-2924 -
obs--96.03 %
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)
12.478-0.26170.06862.2107-0.1970.93520.08030.3360.0871-0.1169-0.13430.0245-0.1617-0.19630.0540.06530.041-0.04310.11630.01480.055841.529-17.91612.279
20.7689-0.0018-0.07273.171-0.16943.180.0907-0.1674-0.17280.1405-0.03420.64820.14040.1427-0.05650.23770.06080.13260.06960.07640.252271.459-53.60854.479
30.9348-0.6288-0.62552.85160.53712.54640.30470.2799-0.1899-0.1816-0.1955-0.02890.0034-0.1075-0.10920.38940.0051-0.00770.1191-0.09180.095857.037-51.721-0.743
42.62790.12780.16741.50190.10781.4467-0.0338-0.24430.042-0.11160.05240.0242-0.25020.3355-0.01860.0494-0.05990.00810.1097-0.00540.121488.114-19.98843.415
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A25 - 417
2X-RAY DIFFRACTION1A500
3X-RAY DIFFRACTION2B25 - 417
4X-RAY DIFFRACTION2B500
5X-RAY DIFFRACTION3C25 - 417
6X-RAY DIFFRACTION3C500
7X-RAY DIFFRACTION4D25 - 417
8X-RAY DIFFRACTION4D500
9X-RAY DIFFRACTION4A601 - 623
10X-RAY DIFFRACTION4B601 - 604
11X-RAY DIFFRACTION4C601 - 604
12X-RAY DIFFRACTION4D601 - 609

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