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- PDB-4yvc: ROCK 1 bound to thiazole inhibitor -

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Basic information

Entry
Database: PDB / ID: 4yvc
TitleROCK 1 bound to thiazole inhibitor
ComponentsRho-associated protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / dimer / dimerization / myosin / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


regulation of angiotensin-activated signaling pathway / apical constriction / podocyte cell migration / Rho-dependent protein serine/threonine kinase activity / positive regulation of phosphatase activity / regulation of keratinocyte differentiation / myoblast migration / positive regulation of connective tissue replacement / membrane to membrane docking / negative regulation of membrane protein ectodomain proteolysis ...regulation of angiotensin-activated signaling pathway / apical constriction / podocyte cell migration / Rho-dependent protein serine/threonine kinase activity / positive regulation of phosphatase activity / regulation of keratinocyte differentiation / 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 / : / regulation of cell junction assembly / positive regulation of dephosphorylation / negative regulation of bicellular tight junction assembly / bleb / negative regulation of phosphorylation / negative regulation of amyloid precursor protein catabolic process / neuron projection arborization / embryonic morphogenesis / bleb assembly / negative regulation of biomineral tissue development / leukocyte tethering or rolling / regulation of synapse maturation / positive regulation of amyloid-beta clearance / actomyosin structure organization / 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 / response to angiotensin / aortic valve morphogenesis / regulation of establishment of cell polarity / RHOBTB1 GTPase cycle / motor neuron apoptotic process / RND3 GTPase cycle / regulation of synaptic vesicle endocytosis / regulation of neuron differentiation / cortical actin cytoskeleton organization / regulation of focal adhesion assembly / leukocyte cell-cell adhesion / leukocyte migration / RHOB GTPase cycle / tau-protein kinase activity / EPHA-mediated growth cone collapse / mRNA destabilization / positive regulation of cardiac muscle hypertrophy / Apoptotic cleavage of cellular proteins / RHOC GTPase cycle / negative regulation of amyloid-beta formation / positive regulation of focal adhesion assembly / mitotic cytokinesis / Rho protein signal transduction / RHOH GTPase cycle / smooth muscle contraction / epithelial to mesenchymal transition / RHOA GTPase cycle / regulation of cell adhesion / canonical NF-kappaB signal transduction / positive regulation of autophagy / regulation of microtubule cytoskeleton organization / ruffle / EPHB-mediated forward signaling / regulation of cell migration / centriole / negative regulation of angiogenesis / blood vessel diameter maintenance / negative regulation of protein binding / protein localization to plasma membrane / regulation of actin cytoskeleton organization / tau protein binding / Schaffer collateral - CA1 synapse / VEGFA-VEGFR2 Pathway / small GTPase binding / 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 / protein phosphorylation / Golgi membrane / protein serine kinase activity / protein serine/threonine kinase activity / Neutrophil degranulation / positive regulation of gene expression / signal transduction / extracellular region / ATP binding / metal ion binding / plasma membrane / cytosol
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) ...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-4KH / Rho-associated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 3.2 Å
AuthorsJacobs, M.D.
Citation
Journal: J.Med.Chem. / Year: 2015
Title: Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors.
Authors: Green, J. / Cao, J. / Bandarage, U.K. / Gao, H. / Court, J. / Marhefka, C. / Jacobs, M. / Taslimi, P. / Newsome, D. / Nakayama, T. / Shah, S. / Rodems, S.
#1: Journal: J. Biol. Chem. / Year: 2006
Title: The structure of dimeric ROCK I reveals the mechanism for ligand selectivity.
Authors: Jacobs, M. / Hayakawa, K. / Swenson, L. / Bellon, S. / Fleming, M. / Taslimi, P. / Doran, J.
History
DepositionMar 19, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 10, 2015Provider: repository / Type: Initial release
Revision 1.1Jun 17, 2015Group: Database references
Revision 1.2Jul 8, 2015Group: Data collection
Revision 1.3Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / diffrn_radiation_wavelength / entity_src_gen / pdbx_initial_refinement_model / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,6234
Polymers96,0252
Non-polymers5992
Water46826
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4290 Å2
ΔGint-26 kcal/mol
Surface area34690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)181.430, 181.430, 91.504
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121

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


Mass: 48012.285 Da / Num. of mol.: 2 / Fragment: N-terminal kinase domain (UNP residues 6-415)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ROCK1 / Plasmid: pBEV10 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q13464, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-4KH / 2-fluoro-N-[4-(pyridin-4-yl)-1,3-thiazol-2-yl]benzamide


Mass: 299.323 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H10FN3OS
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 26 / 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: 4.51 Å3/Da / Density % sol: 72.71 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 0.45 mM protein, 5% PEG3350, 100 mM MES, 50 mM calcium chloride, 10 mM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jan 28, 2003
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 3.2→20 Å / Num. obs: 27010 / % possible obs: 93.8 % / Biso Wilson estimate: 84.09 Å2 / Rmerge(I) obs: 0.084 / Χ2: 1.191 / Net I/av σ(I): 16.916 / Net I/σ(I): 8.9 / Num. measured all: 131464
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique allΧ2Diffraction-IDRejects% possible all
3.2-3.250.41813390.821093.4
3.25-3.310.37313360.8671094.1
3.31-3.380.33113490.9261093.7
3.38-3.450.29913360.9561094.5
3.45-3.520.24313440.9571093.7
3.52-3.60.21213230.981094.8
3.6-3.690.20213791.0551094.8
3.69-3.790.15413501.0491094.5
3.79-3.90.13413561.0771094.8
3.9-4.030.12513451.191094.7
4.03-4.170.10113421.2021093.5
4.17-4.330.08913531.4611094.6
4.33-4.530.07713421.4641093.7
4.53-4.770.07213621.4371094.8
4.77-5.060.07113621.4071094
5.06-5.440.06713451.4811093.6
5.44-5.980.06413601.3361093.4
5.98-6.810.0613511.2711093
6.81-8.470.04613581.3521092
8.47-200.03413781.2331090.8

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Processing

Software
NameVersionClassification
BUSTER-TNTBUSTER 2.11.6refinement
DENZOdata reduction
SCALEPACKdata scaling
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 2ETR

2etr


Resolution: 3.2→19.87 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.9114 / SU R Cruickshank DPI: 1.573 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.165 / SU Rfree Blow DPI: 0.343 / SU Rfree Cruickshank DPI: 0.354
RfactorNum. reflection% reflectionSelection details
Rfree0.2206 1281 4.79 %RANDOM
Rwork0.1918 ---
obs0.1932 26720 92.86 %-
Displacement parametersBiso max: 157.28 Å2 / Biso mean: 76.14 Å2 / Biso min: 21.79 Å2
Baniso -1Baniso -2Baniso -3
1--1.3782 Å20 Å20 Å2
2---1.3782 Å20 Å2
3---2.7564 Å2
Refine analyzeLuzzati coordinate error obs: 0.587 Å
Refinement stepCycle: final / Resolution: 3.2→19.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6339 0 42 26 6407
Biso mean--79.4 55.04 -
Num. residues----780
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2288SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes175HARMONIC2
X-RAY DIFFRACTIONt_gen_planes940HARMONIC5
X-RAY DIFFRACTIONt_it6554HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion800SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7829SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6554HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8854HARMONIC21.1
X-RAY DIFFRACTIONt_omega_torsion2.8
X-RAY DIFFRACTIONt_other_torsion21.37
LS refinement shellResolution: 3.2→3.33 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.3692 146 4.94 %
Rwork0.2496 2809 -
all0.255 2955 -
obs--92.86 %
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)
12.8034-0.19340.4132.4286-0.96651.61920.001-0.3391-0.29880.01940.07870.3977-0.0672-0.3991-0.0796-0.10880.13170.11140.0901-0.0839-0.136425.2622117.096727.5866
24.2571-1.47540.47310.64880.18851.1988-0.0572-0.6475-0.54550.14140.10240.08890.0261-0.3053-0.0451-0.08190.14150.05960.05190.0657-0.026442.487103.490227.4361
32.9092-0.08310.1982.10080.54492.97260.1220.02320.1714-0.12620.0475-0.3866-0.31180.3809-0.1695-0.03540.08180.0848-0.1095-0.028-0.103868.0693109.354526.987
43.15910.30460.44432.3743-0.1940.59040.1082-0.5418-0.29710.0642-0.133-0.11050.165-0.32760.0248-0.10750.11930.02180.1058-0.0477-0.150540.2168104.430730.7209
52.5041-1.7612-0.80413.40010.28770.72730.1397-0.46730.1160.04930.0176-0.0298-0.42780.2434-0.1573-0.14660.07330.14240.1198-0.0904-0.144326.0767122.636826.3846
64.7827-1.01880.5262.42740.49731.94690.1085-0.41660.5655-0.11520.1775-0.27410.0070.3287-0.2861-0.01840.14530.1485-0.031-0.0897-0.10138.168133.929121.2865
73.1816-0.1335-0.44772.8955-0.58233.5323-0.01010.1292-0.4571-0.15470.03950.28950.4713-0.0025-0.02940.10820.08320.0047-0.30550.0492-0.0606-16.0297125.80621.138
83.4803-0.23971.09212.4742-0.12770.8139-0.1553-0.09040.2930.19290.2264-0.1468-0.30910.4467-0.07110.08080.16730.20050.0031-0.0433-0.235210.0543135.366925.3658
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|6 - 71}A6 - 71
2X-RAY DIFFRACTION2{A|72 - 157}A72 - 157
3X-RAY DIFFRACTION3{A|158 - 356}A158 - 356
4X-RAY DIFFRACTION4{A|357 - 405}A357 - 405
5X-RAY DIFFRACTION5{B|5 - 71}B5 - 71
6X-RAY DIFFRACTION6{B|72 - 157}B72 - 157
7X-RAY DIFFRACTION7{B|158 - 356}B158 - 356
8X-RAY DIFFRACTION8{B|357 - 402}B357 - 402

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