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- PDB-5hvu: Rho-associated protein kinase 1 (ROCK 1) in complex with a pyridi... -

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Basic information

Entry
Database: PDB / ID: 5hvu
TitleRho-associated protein kinase 1 (ROCK 1) in complex with a pyridine thiazole piperidine inhibitor
ComponentsRho-associated protein kinase 1
KeywordsTransferase/transferase inhibitor / kinase / inhibitor / complex / solubilizing group / Transferase-transferase inhibitor complex
Function / homology
Function and homology information


apical constriction / podocyte cell migration / regulation of angiotensin-activated signaling pathway / 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 ...apical constriction / podocyte cell migration / regulation of angiotensin-activated signaling pathway / 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 / Rho-dependent protein serine/threonine kinase activity / bleb / negative regulation of amyloid precursor protein catabolic process / embryonic morphogenesis / bleb assembly / neuron projection arborization / leukocyte tethering or rolling / regulation of cell motility / negative regulation of biomineral tissue development / positive regulation of amyloid-beta clearance / regulation of establishment of endothelial barrier / response to angiotensin / 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 / aortic valve morphogenesis / cortical actin cytoskeleton organization / RHOBTB1 GTPase cycle / regulation of neuron differentiation / motor neuron apoptotic process / RND3 GTPase cycle / negative regulation of bicellular tight junction assembly / 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 / positive regulation of cardiac muscle hypertrophy / Apoptotic cleavage of cellular proteins / RHOC GTPase cycle / mRNA destabilization / negative regulation of amyloid-beta formation / mitotic cytokinesis / RHOH GTPase cycle / smooth muscle contraction / epithelial to mesenchymal transition / RHOA GTPase cycle / positive regulation of focal adhesion assembly / regulation of synaptic vesicle endocytosis / regulation of cell adhesion / negative regulation of protein binding / Rho protein signal transduction / ruffle / EPHB-mediated forward signaling / positive regulation of autophagy / centriole / regulation of microtubule cytoskeleton organization / regulation of cell migration / negative regulation of angiogenesis / blood vessel diameter maintenance / protein localization to plasma membrane / regulation of actin cytoskeleton organization / peptidyl-serine phosphorylation / tau protein binding / small GTPase binding / VEGFA-VEGFR2 Pathway / Schaffer collateral - CA1 synapse / cytoplasmic stress granule / neuron projection development / G alpha (12/13) signalling events / lamellipodium / actin cytoskeleton organization / secretory granule lumen / Potential therapeutics for SARS / cytoskeleton / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / intracellular signal transduction / Golgi membrane / protein serine kinase activity / protein serine/threonine kinase activity / Neutrophil degranulation / positive regulation of gene expression / signal transduction / extracellular region / zinc ion binding / ATP binding / plasma membrane / cytosol / cytoplasm
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. / MRCK kinase PH domain / : / HR1 rho-binding domain / REM-1 domain profile. / Zinc finger phorbol-ester/DAG-type profile. ...Rho-associated protein kinase 1, HR1 / ROCK, Rho binding domain / Rho-associated protein kinase 1/2 / Rho Binding / Rho-binding (RhoBD) domain profile. / MRCK kinase PH domain / : / 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-65R / Rho-associated protein kinase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.8 Å
AuthorsJacobs, M.J.
CitationJournal: 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
DepositionJan 28, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 8, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2017Group: Author supporting evidence / Category: pdbx_struct_assembly_auth_evidence
Revision 1.2Jul 18, 2018Group: Data collection / Database references / Category: citation
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.pdbx_database_id_PubMed / _citation.title / _citation.year
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)96,8984
Polymers96,0252
Non-polymers8732
Water3,387188
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: equilibrium centrifugation
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4300 Å2
ΔGint-27 kcal/mol
Surface area35450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)181.820, 181.820, 90.600
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
DetailsDimer confirmed by analytical ultracentrifugation

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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: Spodoptera frugiperda (fall armyworm) / Strain (production host): High-5
References: UniProt: Q13464, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-65R / 2-{3-[3-(piperidin-4-yl)propoxy]phenyl}-N-[4-(pyridin-4-yl)-1,3-thiazol-2-yl]acetamide


Mass: 436.570 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H28N4O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 4.5 Å3/Da / Density % sol: 72.68 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 4.5% PEG3350, 100mM MES, pH 5.5, 50mM CaCl2, 10mM DTT, 0.45 mM protein, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 120 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 2, 2003
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→29.75 Å / Num. all: 42634 / Num. obs: 42080 / % possible obs: 98.7 % / Redundancy: 6.53 % / Biso Wilson estimate: 91.86 Å2 / Rmerge(I) obs: 0.053 / Rrim(I) all: 0.053 / Χ2: 0.91 / Net I/σ(I): 17.1 / Num. measured all: 289174 / Scaling rejects: 14460
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2Rejects% possible all
2.8-2.96.250.3114.62817042161.19181899.9
2.9-3.026.390.2455.82853342111.1161899.8
3.02-3.156.430.1847.32864342111.03157999.5
3.15-3.326.510.1359.32885642010.97148799.3
3.32-3.536.570.1122904941760.87159898.5
3.53-3.86.670.07615.32922141640.83142898.1
3.8-4.186.720.05720.42937041680.83137297.9
4.18-4.786.660.04425.52925641780.81144297.5
4.78-6.026.670.03928.72926042100.77116198
6.02-29.756.410.02541.12881643450.7995798.3

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Processing

Software
NameVersionClassification
BUSTER-TNT2.11.6refinement
d*TREK8.0SSIdata reduction
d*TREK8.0SSIdata scaling
PDB_EXTRACT3.2data extraction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2ETR without igands

2etr


Resolution: 2.8→29.75 Å / Cor.coef. Fo:Fc: 0.915 / Cor.coef. Fo:Fc free: 0.908 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.436 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.429 / SU Rfree Blow DPI: 0.271 / SU Rfree Cruickshank DPI: 0.276
RfactorNum. reflection% reflectionSelection details
Rfree0.248 2036 4.84 %RANDOM
Rwork0.238 ---
obs0.239 42033 98.6 %-
Displacement parametersBiso max: 177.97 Å2 / Biso mean: 75.02 Å2 / Biso min: 30 Å2
Baniso -1Baniso -2Baniso -3
1--1.4559 Å20 Å20 Å2
2---1.4559 Å20 Å2
3---2.9117 Å2
Refine analyzeLuzzati coordinate error obs: 0.43 Å
Refinement stepCycle: final / Resolution: 2.8→29.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6378 0 62 188 6628
Biso mean--61.39 66.35 -
Num. residues----788
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2301SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes175HARMONIC2
X-RAY DIFFRACTIONt_gen_planes947HARMONIC5
X-RAY DIFFRACTIONt_it6600HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion805SEMIHARMONIC5
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_contact7485SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6600HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg8917HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion2.55
X-RAY DIFFRACTIONt_other_torsion19.08
LS refinement shellResolution: 2.8→2.87 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.328 176 5.66 %
Rwork0.273 2934 -
all-3110 -
obs--99.59 %
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)
13.4722-1.07790.3980.94620.05781.266-0.0463-0.4413-0.22150.03840.12820.0005-0.1896-0.2486-0.0819-0.08230.13850.0486-0.05010.0637-0.247551.581109.132127.4949
23.2607-0.8935-0.68280.94630.07090.7223-0.0315-0.2613-0.0311-0.06940.10440.08750.20230.3726-0.07290.01060.16420.0301-0.0992-0.0441-0.24670.093128.440322.4082
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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