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- PDB-3ndm: Crystal structure of Rho-Associated Protein Kinase (ROCK1) with a... -

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Basic information

Entry
Database: PDB / ID: 3ndm
TitleCrystal structure of Rho-Associated Protein Kinase (ROCK1) with a potent isoquinolone derivative
ComponentsRho-Associated Protein Kinase (ROCK1)
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Rho kinase / phosphorylation / dimerization / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


apical constriction / podocyte cell migration / regulation of angiotensin-activated signaling pathway / myoblast migration / membrane to membrane docking / regulation of keratinocyte differentiation / negative regulation of membrane protein ectodomain proteolysis / positive regulation of connective tissue replacement / response to transforming growth factor beta / regulation of cell junction assembly ...apical constriction / podocyte cell migration / regulation of angiotensin-activated signaling pathway / myoblast migration / membrane to membrane docking / regulation of keratinocyte differentiation / negative regulation of membrane protein ectodomain proteolysis / positive regulation of connective tissue replacement / response to transforming growth factor beta / regulation of cell junction assembly / bleb / negative regulation of amyloid precursor protein catabolic process / embryonic morphogenesis / bleb assembly / neuron projection arborization / leukocyte tethering or rolling / negative regulation of biomineral tissue development / regulation of cell motility / positive regulation of amyloid-beta clearance / regulation of establishment of endothelial barrier / response to angiotensin / regulation of synapse maturation / negative regulation of motor neuron apoptotic process / RHO GTPases Activate ROCKs / regulation of stress fiber assembly / actomyosin structure organization / Sema4D induced cell migration and growth-cone collapse / aortic valve morphogenesis / cortical actin cytoskeleton organization / RHOBTB1 GTPase cycle / regulation of neuron differentiation / motor neuron apoptotic process / RND3 GTPase cycle / negative regulation of bicellular tight junction assembly / regulation of establishment of cell polarity / tau-protein kinase activity / regulation of focal adhesion assembly / leukocyte migration / leukocyte cell-cell adhesion / RHOB GTPase cycle / EPHA-mediated growth cone collapse / positive regulation of cardiac muscle hypertrophy / Apoptotic cleavage of cellular proteins / RHOC GTPase cycle / mRNA destabilization / negative regulation of amyloid-beta formation / mitotic cytokinesis / RHOH GTPase cycle / smooth muscle contraction / epithelial to mesenchymal transition / RHOA GTPase cycle / positive regulation of focal adhesion assembly / regulation of synaptic vesicle endocytosis / Rho protein signal transduction / regulation of cell adhesion / negative regulation of protein binding / ruffle / EPHB-mediated forward signaling / centriole / positive regulation of autophagy / regulation of microtubule cytoskeleton organization / regulation of cell migration / negative regulation of angiogenesis / blood vessel diameter maintenance / Rho-dependent protein serine/threonine kinase activity / protein localization to plasma membrane / regulation of actin cytoskeleton organization / tau protein binding / small GTPase binding / VEGFA-VEGFR2 Pathway / Schaffer collateral - CA1 synapse / cytoplasmic stress granule / neuron projection development / peptidyl-serine phosphorylation / G alpha (12/13) signalling events / lamellipodium / actin cytoskeleton organization / secretory granule lumen / Potential therapeutics for SARS / cytoskeleton / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / intracellular signal transduction / Golgi membrane / protein serine kinase activity / protein serine/threonine kinase activity / Neutrophil degranulation / positive regulation of gene expression / signal transduction / extracellular region / zinc ion binding / ATP binding / plasma membrane / cytosol / cytoplasm
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. / MRCK kinase PH domain / : / HR1 rho-binding domain / REM-1 domain profile. / Zinc finger phorbol-ester/DAG-type profile. ...Rho-associated protein kinase 1, HR1 / ROCK, Rho binding domain / Rho-associated protein kinase 1/2 / Rho Binding / Rho-binding (RhoBD) domain profile. / MRCK kinase PH domain / : / 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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-3ND / Rho-associated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.3 Å
AuthorsLi, X.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 3, aryl substituted pyrrolidines.
Authors: Bosanac, T. / Hickey, E.R. / Ginn, J. / Kashem, M. / Kerr, S. / Kugler, S. / Li, X. / Olague, A. / Schlyer, S. / Young, E.R.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: part 2, optimization for blood pressure reduction in spontaneously hypertensive rats.
Authors: Ginn, J.D. / Bosanac, T. / Chen, R. / Cywin, C. / Hickey, E. / Kashem, M. / Kerr, S. / Kugler, S. / Li, X. / Prokopowicz, A. / Schlyer, S. / Smith, J.D. / Turner, M.R. / Wu, F. / Young, E.R.
History
DepositionJun 7, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 8, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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 (ROCK1)
B: Rho-Associated Protein Kinase (ROCK1)
C: Rho-Associated Protein Kinase (ROCK1)
D: Rho-Associated Protein Kinase (ROCK1)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)193,2567
Polymers192,0494
Non-polymers1,2073
Water1,17165
1
A: Rho-Associated Protein Kinase (ROCK1)
B: Rho-Associated Protein Kinase (ROCK1)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,4273
Polymers96,0252
Non-polymers4021
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Rho-Associated Protein Kinase (ROCK1)
D: Rho-Associated Protein Kinase (ROCK1)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,8294
Polymers96,0252
Non-polymers8052
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)162.784, 83.553, 177.962
Angle α, β, γ (deg.)90.00, 119.95, 90.00
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11D
21C
31A
12D
22B
13D
23B
33C

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection detailsAuth asym-IDAuth seq-ID
111chain D and (resseq 10:165 or resseq 175:248 or resseq...D10 - 165
121chain D and (resseq 10:165 or resseq 175:248 or resseq...D175 - 248
131chain D and (resseq 10:165 or resseq 175:248 or resseq...D258 - 298
141chain D and (resseq 10:165 or resseq 175:248 or resseq...D307 - 370
151chain D and (resseq 10:165 or resseq 175:248 or resseq...D380 - 401
211chain C and (resseq 10:165 or resseq 175:248 or resseq...C10 - 165
221chain C and (resseq 10:165 or resseq 175:248 or resseq...C175 - 248
231chain C and (resseq 10:165 or resseq 175:248 or resseq...C258 - 298
241chain C and (resseq 10:165 or resseq 175:248 or resseq...C307 - 370
251chain C and (resseq 10:165 or resseq 175:248 or resseq...C380 - 401
311chain A and (resseq 10:165 or resseq 175:248 or resseq...A10 - 165
321chain A and (resseq 10:165 or resseq 175:248 or resseq...A175 - 248
331chain A and (resseq 10:165 or resseq 175:248 or resseq...A258 - 298
341chain A and (resseq 10:165 or resseq 175:248 or resseq...A307 - 370
351chain A and (resseq 10:165 or resseq 175:248 or resseq...A380 - 401
112chain D and (resseq 10:401) and backboneD0
212chain B and (resseq 10:401) and backboneB0
113chain D and resseq 900D900
213chain B and resseq 900B900
313chain C and resseq 900C900

NCS ensembles :
ID
1
2
3

NCS oper:
IDCodeMatrixVector
1given(-0.864385, 0.50223, -0.024571), (0.487817, 0.825724, -0.283221), (-0.121953, -0.256798, -0.95874)-44.9361, 28.8339, 112.181
2given(0.950116, -0.308898, 0.043137), (-0.253624, -0.845679, -0.469576), (0.181531, 0.435211, -0.881838)39.861198, 19.9151, 75.005203
3given(-0.927647, -0.293616, -0.230784), (0.312475, -0.948658, -0.049073), (-0.204526, -0.117637, 0.971767)-67.833504, 48.086399, 30.6423
4given(-0.92022, -0.313447, -0.234408), (0.333454, -0.94143, -0.050182), (-0.204949, -0.124343, 0.970842)-66.873901, 49.288502, 30.321199
5given(-0.842489, 0.517679, 0.149065), (0.448551, 0.827342, -0.338094), (-0.298352, -0.217978, -0.929232)-48.953701, 28.9687, 105.705002

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Components

#1: Protein
Rho-Associated Protein Kinase (ROCK1) / ROCK1


Mass: 48012.285 Da / Num. of mol.: 4 / Fragment: N-TERMINAL AND KINASE DOMAIN, RESIDUES 6-415
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q13464, EC: 2.7.1.37
#2: Chemical ChemComp-3ND / (3S,4R)-N-(7-chloro-1-oxo-1,4-dihydroisoquinolin-6-yl)-4-(4-chlorophenyl)pyrrolidine-3-carboxamide


Mass: 402.274 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C20H17Cl2N3O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 65 / 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: 2.73 Å3/Da / Density % sol: 54.95 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 8.5% PEG3350, 0.1M MES, 50 mM CaCl2, pH 6.0, vapor diffusion, hanging drop, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: May 10, 2007
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.3→46.95 Å / Num. all: 31473 / Num. obs: 31334 / % possible obs: 99.6 % / Observed criterion σ(F): 1.7 / Observed criterion σ(I): 1.7 / Redundancy: 3.77 % / Rmerge(I) obs: 0.092 / Net I/σ(I): 7.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
3.3-3.423.750.6491.7199.7
3.42-3.553.840.55621100
3.55-3.723.820.4082.91100
3.72-3.913.820.2993.81100
3.91-4.163.810.2025.11100
4.16-4.483.80.146.71100
4.48-4.933.810.1138.31100
4.93-5.643.80.0959.11100
5.64-7.13.750.07511.8199.9
7.1-46.953.520.04623.6196.2

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Processing

Software
NameVersionClassificationNB
d*TREK9.6Ldata scaling
PHENIX1.6.1_357refinement
PDB_EXTRACT3.1data extraction
MAR345dtbdata collection
d*TREKdata reduction
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.3→42.527 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 0.51 / Isotropic thermal model: Isotropic / σ(F): 1.37 / Phase error: 35.23 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3105 1402 4.48 %
Rwork0.2409 --
obs0.244 31325 99.54 %
all-31334 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 167.506 Å2 / ksol: 0.334 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-1.854 Å20 Å25.4019 Å2
2--0.042 Å20 Å2
3----1.896 Å2
Refinement stepCycle: LAST / Resolution: 3.3→42.527 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12600 0 81 65 12746
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0112989
X-RAY DIFFRACTIONf_angle_d1.26917545
X-RAY DIFFRACTIONf_dihedral_angle_d17.5544816
X-RAY DIFFRACTIONf_chiral_restr0.0781852
X-RAY DIFFRACTIONf_plane_restr0.0062260
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDTypeRms dev position (Å)
11D1356X-RAY DIFFRACTIONPOSITIONAL0.169
12C1356X-RAY DIFFRACTIONPOSITIONAL0.169
13A1428X-RAY DIFFRACTIONPOSITIONAL0.176
21D1568X-RAY DIFFRACTIONPOSITIONAL0.209
22B1568X-RAY DIFFRACTIONPOSITIONAL0.209
31D27X-RAY DIFFRACTIONPOSITIONAL0.117
32B27X-RAY DIFFRACTIONPOSITIONAL0.117
33C27X-RAY DIFFRACTIONPOSITIONAL0.055
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.3-3.41790.37191510.36412966X-RAY DIFFRACTION100
3.4179-3.55470.40671320.36082997X-RAY DIFFRACTION100
3.5547-3.71640.36441420.32362966X-RAY DIFFRACTION100
3.7164-3.91220.38861340.3022993X-RAY DIFFRACTION100
3.9122-4.15710.33811610.2633006X-RAY DIFFRACTION100
4.1571-4.47780.31411430.23752929X-RAY DIFFRACTION100
4.4778-4.92780.29461520.22033001X-RAY DIFFRACTION100
4.9278-5.63950.28331200.21163031X-RAY DIFFRACTION100
5.6395-7.09980.29041490.1973034X-RAY DIFFRACTION100
7.0998-42.53030.24211180.18253000X-RAY DIFFRACTION96

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