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- PDB-5kkt: ROCK 1 bound to azaindole thiazole piperazine inhibitor -

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Basic information

Entry
Database: PDB / ID: 5kkt
TitleROCK 1 bound to azaindole thiazole piperazine inhibitor
ComponentsRho-associated protein kinase 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / inhibitor / phosphorylation / 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-6U2 / Rho-associated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.8 Å
AuthorsJacobs, M.D.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2018
Title: ROCK inhibitors 3: Design, synthesis and structure-activity relationships of 7-azaindole-based Rho kinase (ROCK) inhibitors
Authors: Bandarage, U.K. / Cao, J. / Come, J.H. / Court, J.J. / Gao, H. / Jacobs, M.D. / Marhefka, C. / Nanthakumar, S. / Green, J.
History
DepositionJun 22, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 28, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Refinement description / Category: software
Revision 1.2Jul 11, 2018Group: Data collection / Database references / Structure summary
Category: citation / citation_author / struct
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _struct.title
Revision 1.3Sep 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)97,0064
Polymers96,0252
Non-polymers9812
Water3,459192
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4320 Å2
ΔGint-28 kcal/mol
Surface area35130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)182.910, 182.910, 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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ROCK1 / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): BTI-TN-5B1-4
References: UniProt: Q13464, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-6U2 / 2-[3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl]-~{N}-[4-(1~{H}-pyrrolo[2,3-b]pyridin-3-yl)-1,3-thiazol-2-yl]ethanamide


Mass: 490.620 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H30N6O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 192 / 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: 4.55 Å3/Da / Density % sol: 72.99 %
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: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 5, 2004
RadiationMonochromator: Liquid Nitrogen cooled Dual Crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.8→29.9 Å / Num. obs: 42532 / % possible obs: 98.6 % / Redundancy: 6.57 % / Biso Wilson estimate: 88.2 Å2 / Rmerge(I) obs: 0.068 / Rrim(I) all: 0.068 / Χ2: 0.92 / Net I/σ(I): 14.7 / Num. measured all: 292615 / Scaling rejects: 13169
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2Rejects% possible all
2.8-2.96.470.3444.82872142631.06112299.9
2.9-3.026.580.2785.62909642591.01108199.8
3.02-3.156.570.2047.12909342640.97107899.8
3.15-3.326.590.1578.72916742440.92118699.4
3.32-3.536.610.1210.82939442460.9131198.6
3.53-3.86.640.09313.32940542180.88140198
3.8-4.186.680.07117.32945841760.87154497.5
4.18-4.786.60.05622.42975942290.88183197.5
4.78-6.026.650.05224.22953642550.85123898
6.02-29.96.310.03433.32898643780.87137797.9

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Processing

Software
NameVersionClassification
BUSTER-TNTrefinement
d*TREK8.0SSIdata scaling
PDB_EXTRACT3.2data extraction
d*TREKdata reduction
BUSTER-TNTphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 2ETR

2etr


Resolution: 2.8→29.81 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.912 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.4 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.393 / SU Rfree Blow DPI: 0.258 / SU Rfree Cruickshank DPI: 0.262
RfactorNum. reflection% reflectionSelection details
Rfree0.237 2076 4.88 %RANDOM
Rwork0.222 ---
obs0.223 42505 98.6 %-
Displacement parametersBiso max: 185.43 Å2 / Biso mean: 75.78 Å2 / Biso min: 35.83 Å2
Baniso -1Baniso -2Baniso -3
1--2.6011 Å20 Å20 Å2
2---2.6011 Å20 Å2
3---5.2023 Å2
Refine analyzeLuzzati coordinate error obs: 0.39 Å
Refinement stepCycle: final / Resolution: 2.8→29.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6357 0 72 192 6621
Biso mean--65.62 68.1 -
Num. residues----783
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2298SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes174HARMONIC2
X-RAY DIFFRACTIONt_gen_planes945HARMONIC5
X-RAY DIFFRACTIONt_it6588HARMONIC20
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_contact7691SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6588HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8902HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion2.81
X-RAY DIFFRACTIONt_other_torsion20.04
LS refinement shellResolution: 2.8→2.87 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.27 144 4.56 %
Rwork0.225 3016 -
all-3160 -
obs--99.84 %
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)
13.1271-0.99710.60331.0541-0.23671.4994-0.1091-0.4119-0.132-0.01970.1556-0.0122-0.2588-0.2666-0.0465-0.06940.15390.066-0.04230.0254-0.312252.3938110.003227.4936
23.2513-1.0145-0.47540.76350.20610.7063-0.0621-0.26340.0402-0.05830.11950.02330.22830.3438-0.05740.06020.20540.0536-0.10260.0055-0.27070.0708129.21622.6605
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A6 - 405
2X-RAY DIFFRACTION2{ B|* }B5 - 402

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