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- PDB-3ncz: X-Ray Co-structure of Rho-Associated Protein Kinase (ROCK1) with ... -

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Basic information

Entry
Database: PDB / ID: 3ncz
TitleX-Ray Co-structure of Rho-Associated Protein Kinase (ROCK1) with a potent 2H-isoquinolin-1-one inhibitor
ComponentsRho-associated protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Rho Kinase / Dimer / Phosphorylation / TRANSFERASE / 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
Chem-3NC / Rho-associated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsLi, X.
CitationJournal: 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 6, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 8, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 17, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.name / _software.version
Revision 1.3Feb 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 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)193,3288
Polymers192,0494
Non-polymers1,2794
Water1,13563
1
A: Rho-associated protein kinase 1
B: Rho-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,6644
Polymers96,0252
Non-polymers6402
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4170 Å2
ΔGint-31 kcal/mol
Surface area36330 Å2
MethodPISA
2
C: Rho-associated protein kinase 1
D: Rho-associated protein kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,6644
Polymers96,0252
Non-polymers6402
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3740 Å2
ΔGint-23 kcal/mol
Surface area36980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)161.439, 80.863, 166.619
Angle α, β, γ (deg.)90.00, 117.22, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


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) / Gene: ROCK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q13464, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-3NC / cis-4-amino-N-(7-chloro-1-oxo-1,2-dihydroisoquinolin-6-yl)cyclohexanecarboxamide


Mass: 319.786 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H18ClN3O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 63 / 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: 2

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Sample preparation

CrystalDensity Matthews: 2.52 Å3/Da / Density % sol: 51.15 %
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

Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 0.8 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Feb 26, 2007
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8 Å / Relative weight: 1
ReflectionResolution: 3→44.45 Å / Num. all: 38534 / Num. obs: 38507 / % possible obs: 99.9 % / Observed criterion σ(F): 1.4 / Observed criterion σ(I): 1.4 / Redundancy: 6.42 % / Biso Wilson estimate: 95.5 Å2 / Rmerge(I) obs: 0.116 / Net I/σ(I): 7.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique all% possible all
3-3.116.540.7271.43846100
3.11-3.236.550.6641.73819100
3.23-3.386.520.5412.23802100
3.38-3.566.440.41733820100
3.56-3.786.380.2834.33840100
3.78-4.076.330.1985.93841100
4.07-4.486.390.1298.23861100
4.48-5.136.410.10210.23842100
5.13-6.466.440.08511.93895100
6.46-44.456.170.04223.6394199.3

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.6.1_357)refinement
CNXrefinement
MAR345dtbdata collection
d*TREKdata reduction
d*TREKdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3→44.118 Å / SU ML: 0.51 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 1.34 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.3278 1926 5 %RANDOM
Rwork0.255 ---
obs0.2587 38500 99.91 %-
all-38507 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 114.196 Å2 / ksol: 0.321 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-0.6952 Å20 Å210.6135 Å2
2---8.6106 Å20 Å2
3---7.9154 Å2
Refinement stepCycle: LAST / Resolution: 3→44.118 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12680 0 88 63 12831
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01213451
X-RAY DIFFRACTIONf_angle_d1.24517669
X-RAY DIFFRACTIONf_dihedral_angle_d17.2674825
X-RAY DIFFRACTIONf_chiral_restr0.0811864
X-RAY DIFFRACTIONf_plane_restr0.0052280
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs% reflection obs (%)
3-3.0750.38361110.3825732684100
3.075-3.15820.42791400.369925992739100
3.1582-3.25110.39651380.374226192757100
3.2511-3.3560.43611340.346626222756100
3.356-3.47590.38651440.319725912735100
3.4759-3.6150.37641210.307526022723100
3.615-3.77940.37151310.290326002731100
3.7794-3.97850.35331480.285425822730100
3.9785-4.22760.35461540.258125962750100
4.2276-4.55370.3371360.231426352771100
4.5537-5.01140.33351250.225526432768100
5.0114-5.73520.32851350.226126152750100
5.7352-7.22070.28491610.227326152776100
7.2207-44.12240.24831480.19312682283099

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