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- PDB-5kks: ROCK 1 bound to azaindole thiazole inhibitor -

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Basic information

Entry
Database: PDB / ID: 5kks
TitleROCK 1 bound to azaindole thiazole 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 / membrane to membrane docking / positive regulation of connective tissue replacement / 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 / membrane to membrane docking / positive regulation of connective tissue replacement / 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 / RHOBTB1 GTPase cycle / regulation of establishment of cell polarity / 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 migration / leukocyte cell-cell adhesion / 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 / RHOA GTPase cycle / epithelial to mesenchymal transition / 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-6U1 / Rho-associated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 3.3 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

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)96,8804
Polymers96,0252
Non-polymers8552
Water1,78399
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4310 Å2
ΔGint-25 kcal/mol
Surface area35340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)182.340, 182.340, 90.620
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-6U1 / 2-[3-(methylsulfonylamino)phenyl]-~{N}-[4-(1~{H}-pyrrolo[2,3-b]pyridin-3-yl)-1,3-thiazol-2-yl]ethanamide


Mass: 427.500 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H17N5O3S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 99 / 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: 4.53 Å3/Da / Density % sol: 72.84 %
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: Feb 20, 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: 3.3→29.82 Å / Num. obs: 25592 / % possible obs: 97.2 % / Redundancy: 6.69 % / Biso Wilson estimate: 102.46 Å2 / Rmerge(I) obs: 0.145 / Rrim(I) all: 0.145 / Χ2: 0.84 / Net I/σ(I): 7.4 / Num. measured all: 178468 / Scaling rejects: 7139
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2Rejects% possible all
3.3-3.426.830.5142.81766325841.042599.6
3.42-3.556.880.4243.21799126070.955199.7
3.55-3.726.870.3713.71799926070.929399.5
3.72-3.916.850.24751794825860.8923699
3.91-4.166.760.19661796825920.8645198.5
4.16-4.486.730.1697.21780025260.8679997.7
4.48-4.926.640.14991792925420.75105496.7
4.92-5.636.650.1089.81810825540.79111596.2
5.63-7.086.460.09310.61776225380.72136895.6
7.08-29.826.250.04718.71730024560.6194789.4

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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: 3.3→29.67 Å / Cor.coef. Fo:Fc: 0.911 / Cor.coef. Fo:Fc free: 0.867 / Rfactor Rfree error: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.418
RfactorNum. reflection% reflectionSelection details
Rfree0.254 1230 4.81 %RANDOM
Rwork0.213 ---
obs0.215 25583 97.1 %-
Displacement parametersBiso max: 190.26 Å2 / Biso mean: 93.4 Å2 / Biso min: 32.83 Å2
Baniso -1Baniso -2Baniso -3
1--2.9871 Å20 Å20 Å2
2---2.9871 Å20 Å2
3---5.9742 Å2
Refine analyzeLuzzati coordinate error obs: 0.43 Å
Refinement stepCycle: final / Resolution: 3.3→29.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6411 0 60 99 6570
Biso mean--87.48 66.64 -
Num. residues----790
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2315SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes177HARMONIC2
X-RAY DIFFRACTIONt_gen_planes954HARMONIC5
X-RAY DIFFRACTIONt_it6629HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion807SEMIHARMONIC5
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_contact7797SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6629HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8963HARMONIC21.13
X-RAY DIFFRACTIONt_omega_torsion2.67
X-RAY DIFFRACTIONt_other_torsion22.39
LS refinement shellResolution: 3.3→3.44 Å / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.272 153 5.2 %
Rwork0.212 2790 -
all-2943 -
obs--99.49 %
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)
13.9946-1.23740.47721.6037-0.09261.5048-0.1261-0.3777-0.10470.05940.17980.0151-0.2689-0.3692-0.0537-0.0580.22560.0649-0.05090.0616-0.32552.2271109.980127.8119
24.0009-1.0847-0.27570.7968-0.15530.7637-0.0508-0.2667-0.0171-0.02250.1279-0.01690.32940.502-0.0770.04180.28170.0661-0.09740.0034-0.2731-0.2032128.905422.9826
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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