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- PDB-4yve: ROCK 1 bound to methoxyphenyl thiazole inhibitor -

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Basic information

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


apical constriction / podocyte cell migration / regulation of angiotensin-activated signaling pathway / positive regulation of phosphatase activity / 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 ...apical constriction / podocyte cell migration / regulation of angiotensin-activated signaling pathway / positive regulation of phosphatase activity / 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 / negative regulation of bicellular tight junction assembly / positive regulation of dephosphorylation / bleb / negative regulation of amyloid precursor protein catabolic process / embryonic morphogenesis / neuron projection arborization / bleb assembly / 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 / 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 / response to angiotensin / aortic valve morphogenesis / cortical actin cytoskeleton organization / motor neuron apoptotic process / RHOBTB1 GTPase cycle / regulation of neuron differentiation / RND3 GTPase cycle / 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 / Apoptotic cleavage of cellular proteins / RHOC GTPase cycle / positive regulation of cardiac muscle hypertrophy / mRNA destabilization / negative regulation of amyloid-beta formation / regulation of synaptic vesicle endocytosis / mitotic cytokinesis / RHOH GTPase cycle / smooth muscle contraction / positive regulation of focal adhesion assembly / RHOA GTPase cycle / epithelial to mesenchymal transition / Rho protein signal transduction / regulation of cell adhesion / ruffle / positive regulation of autophagy / EPHB-mediated forward signaling / negative regulation of protein binding / centriole / regulation of microtubule cytoskeleton organization / negative regulation of angiogenesis / regulation of cell migration / blood vessel diameter maintenance / protein localization to plasma membrane / regulation of actin cytoskeleton organization / Schaffer collateral - CA1 synapse / small GTPase binding / tau protein binding / VEGFA-VEGFR2 Pathway / cytoplasmic stress granule / neuron projection development / G alpha (12/13) signalling events / lamellipodium / peptidyl-serine phosphorylation / actin cytoskeleton organization / secretory granule lumen / Potential therapeutics for SARS / eukaryotic translation initiation factor 2alpha kinase activity / cytoskeleton / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity
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 / 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-4KK / Rho-associated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 3.4 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.
#2: Journal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: ROCK inhibitors 2. Improving potency, selectivity and solubility through the application of rationally designed solubilizing groups.
Authors: Gao, H. / Marhefka, C. / Jacobs, M.D. / Cao, J. / Bandarage, U.K. / Green, 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 1.3Jul 18, 2018Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy
Category: citation / citation_author ...citation / citation_author / entity_src_gen / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_assembly.oligomeric_details ..._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
Revision 1.4Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)96,6754
Polymers96,0252
Non-polymers6512
Water1629
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4290 Å2
ΔGint-30 kcal/mol
Surface area34870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)181.980, 181.980, 90.560
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-4KK / 2-(3-methoxyphenyl)-N-[4-(pyridin-4-yl)-1,3-thiazol-2-yl]acetamide


Mass: 325.385 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H15N3O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 9 / 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: 3.4→29.78 Å / Num. obs: 23765 / % possible obs: 99 % / Redundancy: 7.41 % / Biso Wilson estimate: 94.4 Å2 / Rmerge(I) obs: 0.155 / Χ2: 2.29 / Net I/σ(I): 4.2 / Num. measured all: 178283 / Scaling rejects: 2109
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2Rejects% possible all
3.4-3.527.510.481.31798323941.326100
3.52-3.667.550.4071.61783123571.924499.7
3.66-3.837.540.3391.91800123752.58999.5
3.83-4.037.520.2932.21773923462.5410299.4
4.03-4.287.480.2282.81788123532.9326998.6
4.28-4.617.460.183.71794923523.2340898.1
4.61-5.077.430.1454.61789823502.5443697.8
5.07-5.87.440.1315.21776023562.1523898.7
5.8-7.297.340.1066.61786024271.784599.6
7.29-29.786.890.05612.21738124551.9947298

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Processing

Software
NameVersionClassification
d*TREK7.1SSIdata reduction
d*TREK7.1SSIdata scaling
BUSTER-TNTBUSTER 2.11.6refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 2ETR

2etr


Resolution: 3.4→19.86 Å / Cor.coef. Fo:Fc: 0.9051 / Cor.coef. Fo:Fc free: 0.8771 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.427
RfactorNum. reflection% reflectionSelection details
Rfree0.2443 1182 5.11 %RANDOM
Rwork0.2178 ---
obs0.2192 23114 96.65 %-
Displacement parametersBiso max: 184.88 Å2 / Biso mean: 85.88 Å2 / Biso min: 20 Å2
Baniso -1Baniso -2Baniso -3
1--7.726 Å20 Å20 Å2
2---7.726 Å20 Å2
3---15.4519 Å2
Refine analyzeLuzzati coordinate error obs: 0.728 Å
Refinement stepCycle: final / Resolution: 3.4→19.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6365 0 46 9 6420
Biso mean--79.6 45.78 -
Num. residues----783
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2297SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes174HARMONIC2
X-RAY DIFFRACTIONt_gen_planes942HARMONIC5
X-RAY DIFFRACTIONt_it6569HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion802SEMIHARMONIC5
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_contact7776SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6569HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8873HARMONIC21.13
X-RAY DIFFRACTIONt_omega_torsion2.75
X-RAY DIFFRACTIONt_other_torsion21.7
LS refinement shellResolution: 3.4→3.55 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.3326 142 5.06 %
Rwork0.2598 2665 -
all0.2634 2807 -
obs--96.65 %
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)
15.1974-1.75310.24011.8035-1.37012.87440.003-0.4737-0.23870.07010.30830.2741-0.0479-0.3235-0.3113-0.05530.16260.11740.1079-0.0113-0.291125.4692117.645327.8067
26.1899-1.10290.64570.7421-0.94120.0068-0.0835-0.7221-0.56220.27310.2238-0.0176-0.1722-0.3954-0.1402-0.03630.16820.06940.12040.1838-0.178242.8875104.63828.3673
33.20350.21610.45912.1540.92453.81110.05010.01050.2129-0.21850.1041-0.4891-0.45020.361-0.1542-0.05150.13870.0486-0.10090.0135-0.132568.2882109.331426.3199
43.88221.60030.88640.697-0.45770.8922-0.0557-0.5361-0.38110.3893-0.0512-0.1554-0.096-0.43610.10690.00240.2217-0.01380.09740.1629-0.249840.2441105.172630.8101
53.691-2.9006-0.88583.10711.58151.6132-0.0213-0.5213-0.00520.15130.1446-0.0223-0.27530.1733-0.1233-0.07730.12180.10980.1330.044-0.275126.3366123.07526.5264
65.9531-1.72880.8131.228-0.45180-0.0884-0.46850.61990.14280.2605-0.10250.02870.4074-0.17210.01850.2640.11080.0647-0.1115-0.20588.5983134.478921.245
73.5398-0.4152-1.08883.8026-0.54874.4558-0.04450.0318-0.49890.00920.00160.24310.610.02850.04290.15980.145-0.0295-0.2911-0.023-0.032-15.6889126.227921.0516
83.8780.16352.75421.2214-0.6117.3026-0.1519-0.27380.4690.22810.2610.14790.09850.5629-0.1091-0.0050.27120.16530.0328-0.0538-0.296410.4802136.321825.6397
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|1 - 71}A1 - 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|1 - 71}B1 - 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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