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- PDB-5u7q: Identification of A New Class of Potent Cdc7 Inhibitors Designed ... -

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Basic information

Entry
Database: PDB / ID: 5u7q
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
Rho-associated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 3.15 Å
AuthorsHoffman, I.D.
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 / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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


Theoretical massNumber of molelcules
Total (without water)181,6034
Polymers181,6034
Non-polymers00
Water18010
1
A: Rho-associated protein kinase 2


Theoretical massNumber of molelcules
Total (without water)45,4011
Polymers45,4011
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Rho-associated protein kinase 2


Theoretical massNumber of molelcules
Total (without water)45,4011
Polymers45,4011
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Rho-associated protein kinase 2


Theoretical massNumber of molelcules
Total (without water)45,4011
Polymers45,4011
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Rho-associated protein kinase 2


Theoretical massNumber of molelcules
Total (without water)45,4011
Polymers45,4011
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
A: Rho-associated protein kinase 2

B: Rho-associated protein kinase 2


Theoretical massNumber of molelcules
Total (without water)90,8012
Polymers90,8012
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_655x+1,y,z1
Buried area3390 Å2
ΔGint-25 kcal/mol
Surface area36170 Å2
MethodPISA
6
C: Rho-associated protein kinase 2

D: Rho-associated protein kinase 2


Theoretical massNumber of molelcules
Total (without water)90,8012
Polymers90,8012
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_556x,y,z+11
Buried area3520 Å2
ΔGint-25 kcal/mol
Surface area36410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.194, 146.463, 112.416
Angle α, β, γ (deg.)90.000, 96.340, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14B
24C
15B
25D
16C
26D

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ARGARGTYRTYRAA28 - 4166 - 394
21ARGARGTYRTYRBB28 - 4166 - 394
12SERSERTYRTYRAA25 - 4163 - 394
22SERSERTYRTYRCC25 - 4163 - 394
13GLNGLNARGARGAA27 - 4175 - 395
23GLNGLNARGARGDD27 - 4175 - 395
14ARGARGTYRTYRBB28 - 4166 - 394
24ARGARGTYRTYRCC28 - 4166 - 394
15ARGARGARGARGBB28 - 4176 - 395
25ARGARGARGARGDD28 - 4176 - 395
16GLNGLNTYRTYRCC27 - 4165 - 394
26GLNGLNTYRTYRDD27 - 4165 - 394

NCS ensembles :
ID
1
2
3
4
5
6

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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: 45400.645 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: Baculovirus expression vector pFastBac1-HM / Strain (production host): Sf9
References: UniProt: O75116, non-specific serine/threonine protein kinase
#2: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 10 / 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: 4.16 Å3/Da / Density % sol: 70.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 1.1 M Sodium malonate pH 7.0, 0.1 M HEPES pH 7.0, 0.5% v/v Jeffamine ED-2001 pH 7.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9764848 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 4, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9764848 Å / Relative weight: 1
ReflectionResolution: 3.15→50 Å / Num. obs: 51367 / % possible obs: 100 % / Redundancy: 4.2 % / Rmerge(I) obs: 0.132 / Χ2: 1 / Net I/σ(I): 6.7 / Num. measured all: 215910
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
3.15-3.240.833199.9
3.2-3.264.10.6751100
3.26-3.334.20.621100
3.33-3.394.20.4841100
3.39-3.474.30.4051100
3.47-3.554.20.3461100
3.55-3.644.30.271100
3.64-3.734.20.221100
3.73-3.844.30.1841100
3.84-3.974.20.1621100
3.97-4.114.20.1361100
4.11-4.274.20.1181100
4.27-4.474.20.1071100
4.47-4.74.20.0991100
4.7-54.20.1021100
5-5.384.20.0981100
5.38-5.934.20.0941100
5.93-6.784.10.0771100
6.78-8.544.20.0541100
8.54-504.10.0421100

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.8.0135refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
PHASERphasing
DENZOdata reduction
SCALEPACKdata scaling
RefinementResolution: 3.15→30 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.906 / SU B: 40.328 / SU ML: 0.303 / SU R Cruickshank DPI: 0.3824 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.381
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2348 2611 5.1 %RANDOM
Rwork0.2048 ---
obs0.2063 48123 97.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 191.35 Å2 / Biso mean: 72.412 Å2 / Biso min: 20.16 Å2
Baniso -1Baniso -2Baniso -3
1-2.78 Å2-0 Å21.3 Å2
2---2.85 Å20 Å2
3----0.21 Å2
Refinement stepCycle: final / Resolution: 3.15→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12530 0 0 10 12540
Biso mean---31.91 -
Num. residues----1546
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01912840
X-RAY DIFFRACTIONr_bond_other_d0.0070.0212086
X-RAY DIFFRACTIONr_angle_refined_deg1.6611.95417355
X-RAY DIFFRACTIONr_angle_other_deg1.565327829
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.11451537
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.06124.069639
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.788152235
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.9091578
X-RAY DIFFRACTIONr_chiral_restr0.0910.21837
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02114469
X-RAY DIFFRACTIONr_gen_planes_other0.0050.023035
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A450340.11
12B450340.11
21A461500.1
22C461500.1
31A452280.11
32D452280.11
41B463140.09
42C463140.09
51B465500.08
52D465500.08
61C458240.09
62D458240.09
LS refinement shellResolution: 3.15→3.198 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.322 157 -
Rwork0.317 2650 -
all-2807 -
obs--73.77 %
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)
13.35511.56041.77281.99132.00632.9516-0.06780.082-0.2099-0.09630.0762-0.4589-0.25960.2508-0.00830.0788-0.0184-0.04240.04140.07070.335259.2756-16.332815.798
23.28120.41410.09272.40550.11242.0623-0.00470.3188-0.0728-0.165-0.03820.2851-0.138-0.38370.04290.05220.0268-0.08180.16940.0220.172731.5575-16.464211.3073
33.7863-1.32011.97222.422-2.40182.7459-0.12960.14230.08940.12610.1820.3211-0.3106-0.1435-0.05240.1676-0.006-0.09730.0673-0.02260.3361-18.239-16.778840.7845
43.4243-0.07610.06361.7688-0.48671.5117-0.0152-0.10530.02710.0755-0.0756-0.3353-0.09890.33850.09080.0996-0.0211-0.06540.2135-0.01740.29029.3449-18.481446.7595
51.7778-1.07621.10841.2237-1.93924.23150.0986-0.2901-0.33890.23040.11140.134-0.09-0.0957-0.20990.5161-0.1105-0.10340.09690.00120.23084.004321.171574.3374
61.52260.113-0.27182.7712-0.02113.10440.05330.2786-0.089-0.28830.0128-0.3856-0.0821-0.0234-0.06610.201-0.04170.01960.1584-0.07150.18749.109821.477546.6344
71.18991.24580.88872.09741.68014.159-0.05250.1937-0.3148-0.38120.20670.03370.2078-0.1964-0.15420.4266-0-0.07580.12920.03450.343935.341121.8367-16.3406
80.79950.3628-0.74852.1682-0.58323.35320.0656-0.0875-0.01330.22680.12640.2495-0.2317-0.1118-0.1920.30060.0632-0.00080.16790.05310.232732.617523.491711.8808
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A25 - 173
2X-RAY DIFFRACTION2A174 - 417
3X-RAY DIFFRACTION3B28 - 173
4X-RAY DIFFRACTION4B174 - 417
5X-RAY DIFFRACTION5C25 - 173
6X-RAY DIFFRACTION6C174 - 417
7X-RAY DIFFRACTION7D27 - 173
8X-RAY DIFFRACTION8D174 - 417

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