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- PDB-3v8s: Human RHO-ASSOCIATED PROTEIN KINASE 1 (ROCK 1) IN COMPLEX WITH IN... -

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Basic information

Entry
Database: PDB / ID: 3v8s
TitleHuman RHO-ASSOCIATED PROTEIN KINASE 1 (ROCK 1) IN COMPLEX WITH INDAZOLE DERIVATIVE (COMPOUND 18)
ComponentsRho-associated protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / KINASE / DIMERIZATION / MYOSIN / TRANSFERASE / INHIBITOR / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


regulation of amyloid-beta formation / regulation of angiotensin-activated signaling pathway / apical constriction / Rho-dependent protein serine/threonine kinase activity / podocyte cell migration / regulation of keratinocyte differentiation / positive regulation of phosphatase activity / myoblast migration / positive regulation of connective tissue replacement / membrane to membrane docking ...regulation of amyloid-beta formation / regulation of angiotensin-activated signaling pathway / apical constriction / Rho-dependent protein serine/threonine kinase activity / podocyte cell migration / regulation of keratinocyte differentiation / positive regulation of phosphatase activity / myoblast migration / positive regulation of connective tissue replacement / membrane to membrane docking / negative regulation of membrane protein ectodomain proteolysis / response to transforming growth factor beta / negative regulation of myosin-light-chain-phosphatase activity / regulation of cell junction assembly / positive regulation of dephosphorylation / negative regulation of bicellular tight junction assembly / regulation of synapse maturation / bleb / positive regulation of amyloid-beta clearance / negative regulation of amyloid precursor protein catabolic process / neuron projection arborization / bleb assembly / embryonic morphogenesis / leukocyte tethering or rolling / negative regulation of biomineral tissue development / negative regulation of phosphorylation / actomyosin structure organization / aspartic-type endopeptidase inhibitor activity / regulation of establishment of endothelial barrier / RHO GTPases Activate ROCKs / negative regulation of motor neuron apoptotic process / 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 / motor neuron apoptotic process / RHOBTB1 GTPase cycle / RND3 GTPase cycle / regulation of synaptic vesicle endocytosis / cortical actin cytoskeleton organization / regulation of neuron differentiation / regulation of focal adhesion assembly / leukocyte cell-cell adhesion / RHOB GTPase cycle / tau-protein kinase activity / leukocyte migration / negative regulation of amyloid-beta formation / EPHA-mediated growth cone collapse / mRNA destabilization / positive regulation of cardiac muscle hypertrophy / RHOC GTPase cycle / Apoptotic cleavage of cellular proteins / positive regulation of focal adhesion assembly / RHOH GTPase cycle / mitotic cytokinesis / Rho protein signal transduction / smooth muscle contraction / RHOA GTPase cycle / epithelial to mesenchymal transition / canonical NF-kappaB signal transduction / regulation of microtubule cytoskeleton organization / positive regulation of autophagy / regulation of cell adhesion / regulation of cell migration / ruffle / EPHB-mediated forward signaling / centriole / blood vessel diameter maintenance / negative regulation of angiogenesis / negative regulation of protein binding / regulation of autophagy / protein localization to plasma membrane / regulation of actin cytoskeleton organization / tau protein binding / Schaffer collateral - CA1 synapse / small GTPase binding / VEGFA-VEGFR2 Pathway / cytoplasmic stress granule / neuron projection development / G alpha (12/13) signalling events / lamellipodium / actin cytoskeleton organization / peptidyl-serine phosphorylation / secretory granule lumen / Potential therapeutics for SARS / positive regulation of MAPK cascade / cytoskeleton / non-specific serine/threonine protein kinase / protein kinase activity / Golgi membrane / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / Neutrophil degranulation / positive regulation of gene expression / signal transduction / extracellular region / ATP binding
Similarity search - Function
Rho-associated protein kinase 1, HR1 / 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 ...Rho-associated protein kinase 1, HR1 / 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
1-(1H-indazol-5-yl)-3-(2-phenylethyl)urea / Rho-associated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.286 Å
AuthorsMartin, M.P. / Zhu, J.-Yi. / Schonbrunn, E.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Fragment-based and structure-guided discovery and optimization of rho kinase inhibitors.
Authors: Li, R. / Martin, M.P. / Liu, Y. / Wang, B. / Patel, R.A. / Zhu, J.Y. / Sun, N. / Pireddu, R. / Lawrence, N.J. / Li, J. / Haura, E.B. / Sung, S.S. / Guida, W.C. / Schonbrunn, E. / Sebti, S.M.
History
DepositionDec 23, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 8, 2012Provider: repository / Type: Initial release
Revision 1.1Mar 21, 2012Group: Database references
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_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 1
B: Rho-associated protein kinase 1
C: Rho-associated protein kinase 1
D: Rho-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)191,0648
Polymers189,9434
Non-polymers1,1214
Water15,709872
1
A: Rho-associated protein kinase 1
B: Rho-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,5324
Polymers94,9712
Non-polymers5612
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3670 Å2
ΔGint-26 kcal/mol
Surface area36930 Å2
MethodPISA
2
C: Rho-associated protein kinase 1
D: Rho-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)95,5324
Polymers94,9712
Non-polymers5612
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3700 Å2
ΔGint-25 kcal/mol
Surface area36850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)151.720, 152.110, 186.140
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-702-

HOH

21A-824-

HOH

31C-820-

HOH

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Components

#1: Protein
Rho-associated protein kinase 1 / Renal carcinoma antigen NY-REN-35 / Rho-associated / coiled-coil-containing protein kinase 1 / Rho- ...Renal carcinoma antigen NY-REN-35 / Rho-associated / coiled-coil-containing protein kinase 1 / Rho-associated / coiled-coil-containing protein kinase I / ROCK-I / p160 ROCK-1 / p160ROCK


Mass: 47485.660 Da / Num. of mol.: 4 / Fragment: RESIDUE 6-415
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ROCK1 / Plasmid: pFB-Dual-PBL / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q13464, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-0HD / 1-(1H-indazol-5-yl)-3-(2-phenylethyl)urea


Mass: 280.324 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H16N4O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 872 / 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: 2.83 Å3/Da / Density % sol: 56.49 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 10 MG/ML ROCK1, 25 MM HEPES PH 7.4, 50 MM MES PH 6.5, 2.5% TACSIMATE PH 7.0, 5% PEG 5000 MME, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 291K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MAR scanner 300 mm plate / Detector: IMAGE PLATE / Date: Nov 28, 2011
RadiationMonochromator: MD2 micro diffractometer / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.286→20 Å / Num. obs: 96308 / % possible obs: 100 % / Redundancy: 9.3 % / Rmerge(I) obs: 0.119 / Net I/σ(I): 34.2
Reflection shellResolution: 2.3→2.34 Å / Rmerge(I) obs: 0.39 / Mean I/σ(I) obs: 5.1 / % possible all: 99.8

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Processing

Software
NameVersionClassification
MOLREPphasing
PHENIX(phenix.refine: 1.7_650)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TV7

3tv7


Resolution: 2.286→19.851 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 23.38 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2361 1938 2.06 %RANDOM
Rwork0.1866 ---
obs0.1876 94051 97.05 %-
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 48.175 Å2 / ksol: 0.357 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-3.6337 Å20 Å2-0 Å2
2--5.5918 Å20 Å2
3----9.2255 Å2
Refinement stepCycle: LAST / Resolution: 2.286→19.851 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12878 0 84 872 13834
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00813276
X-RAY DIFFRACTIONf_angle_d1.25517932
X-RAY DIFFRACTIONf_dihedral_angle_d15.1064926
X-RAY DIFFRACTIONf_chiral_restr0.0981880
X-RAY DIFFRACTIONf_plane_restr0.0062326
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.286-2.34310.21871220.21455643X-RAY DIFFRACTION85
2.3431-2.40630.31351360.20766353X-RAY DIFFRACTION95
2.4063-2.4770.30471410.21316378X-RAY DIFFRACTION95
2.477-2.55680.25941390.20546497X-RAY DIFFRACTION96
2.5568-2.6480.27221350.20956394X-RAY DIFFRACTION96
2.648-2.75370.29441330.20936580X-RAY DIFFRACTION97
2.7537-2.87870.27891390.20786599X-RAY DIFFRACTION98
2.8787-3.030.23821370.20576672X-RAY DIFFRACTION99
3.03-3.21910.25541370.20356733X-RAY DIFFRACTION99
3.2191-3.46640.28591390.19576809X-RAY DIFFRACTION100
3.4664-3.8130.20911420.1756758X-RAY DIFFRACTION100
3.813-4.35970.23261410.15096813X-RAY DIFFRACTION100
4.3597-5.47360.18261460.16086880X-RAY DIFFRACTION100
5.4736-19.85190.19161510.197004X-RAY DIFFRACTION100

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