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- PDB-4l6q: ROCK2 in complex with benzoxaborole -

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Basic information

Entry
Database: PDB / ID: 4l6q
TitleROCK2 in complex with benzoxaborole
ComponentsRho-associated protein kinase 2
KeywordsTransferase/Transferase Inhibitor / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


cellular response to acetylcholine / positive regulation of connective tissue growth factor production / positive regulation of amyloid precursor protein catabolic process / positive regulation of centrosome duplication / regulation of angiotensin-activated signaling pathway / Rho-dependent protein serine/threonine kinase activity / negative regulation of protein localization to lysosome / regulation of keratinocyte differentiation / positive regulation of connective tissue replacement / positive regulation of fibroblast growth factor production ...cellular response to acetylcholine / positive regulation of connective tissue growth factor production / positive regulation of amyloid precursor protein catabolic process / positive regulation of centrosome duplication / regulation of angiotensin-activated signaling pathway / Rho-dependent protein serine/threonine kinase activity / negative regulation of protein localization to lysosome / regulation of keratinocyte differentiation / positive regulation of connective tissue replacement / positive regulation of fibroblast growth factor production / positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process / response to transforming growth factor beta / negative regulation of myosin-light-chain-phosphatase activity / regulation of nervous system process / regulation of cell junction assembly / negative regulation of bicellular tight junction assembly / regulation of protein metabolic process / modulation by host of viral process / regulation of cellular response to hypoxia / positive regulation of protein localization to early endosome / embryonic morphogenesis / negative regulation of nitric oxide biosynthetic process / negative regulation of biomineral tissue development / cellular response to testosterone stimulus / actomyosin structure organization / regulation of establishment of endothelial barrier / RHO GTPases Activate ROCKs / regulation of stress fiber assembly / regulation of cell motility / Sema4D induced cell migration and growth-cone collapse / aortic valve morphogenesis / response to angiotensin / regulation of establishment of cell polarity / RHOBTB1 GTPase cycle / cortical actin cytoskeleton organization / regulation of focal adhesion assembly / RHOB GTPase cycle / positive regulation of amyloid-beta formation / tau-protein kinase activity / EPHA-mediated growth cone collapse / mRNA destabilization / positive regulation of cardiac muscle hypertrophy / RHOC GTPase cycle / RHOH GTPase cycle / centrosome duplication / mitotic cytokinesis / Rho protein signal transduction / smooth muscle contraction / RHOA GTPase cycle / epithelial to mesenchymal transition / canonical NF-kappaB signal transduction / regulation of cell adhesion / positive regulation of stress fiber assembly / EPHB-mediated forward signaling / blood vessel diameter maintenance / negative regulation of angiogenesis / positive regulation of endothelial cell migration / response to ischemia / protein localization to plasma membrane / regulation of actin cytoskeleton organization / peptidyl-threonine phosphorylation / tau protein binding / regulation of circadian rhythm / cytoplasmic ribonucleoprotein granule / small GTPase binding / VEGFA-VEGFR2 Pathway / rhythmic process / G alpha (12/13) signalling events / actin cytoskeleton organization / peptidyl-serine phosphorylation / Potential therapeutics for SARS / positive regulation of MAPK cascade / cytoskeleton / non-specific serine/threonine protein kinase / positive regulation of cell migration / positive regulation of protein phosphorylation / negative regulation of gene expression / protein phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / positive regulation of gene expression / structural molecule activity / RNA binding / ATP binding / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / Rho-associated protein kinase 2, HR1 domain / 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 2, HR1 domain / 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-1WU / Rho-associated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.79 Å
AuthorsRock, F. / Jarnagin, K.
CitationJournal: J.Pharmacol.Exp.Ther. / Year: 2013
Title: Linking phenotype to kinase: identification of a novel benzoxaborole hinge-binding motif for kinase inhibition and development of high-potency rho kinase inhibitors.
Authors: Akama, T. / Dong, C. / Virtucio, C. / Sullivan, D. / Zhou, Y. / Zhang, Y.K. / Rock, F. / Freund, Y. / Liu, L. / Bu, W. / Wu, A. / Fan, X.Q. / Jarnagin, K.
History
DepositionJun 12, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2013Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2013Group: Database references
Revision 1.2Apr 18, 2018Group: Advisory / Data collection / Category: diffrn_detector / pdbx_unobs_or_zero_occ_atoms / Item: _diffrn_detector.detector
Revision 1.3Feb 28, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Rho-associated protein kinase 2
B: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,3464
Polymers91,8002
Non-polymers5462
Water1086
1
A: Rho-associated protein kinase 2
hetero molecules

A: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,3464
Polymers91,8002
Non-polymers5462
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_554-x,y,-z-11
Buried area3350 Å2
ΔGint-27 kcal/mol
Surface area35960 Å2
MethodPISA
2
B: Rho-associated protein kinase 2
hetero molecules

B: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,3464
Polymers91,8002
Non-polymers5462
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_554-x,y,-z-11
Buried area3420 Å2
ΔGint-26 kcal/mol
Surface area36120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)136.465, 147.518, 91.214
Angle α, β, γ (deg.)90.00, 125.17, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Rho-associated protein kinase 2 / Rho kinase 2 / Rho-associated / coiled-coil-containing protein kinase 2 / ROCK-II / p164 ROCK-2


Mass: 45900.125 Da / Num. of mol.: 2 / Fragment: UNP residues 19-417
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ROCK2, KIAA0619 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O75116, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-1WU / 6-[4-(aminomethyl)-2-fluorophenoxy]-2,1-benzoxaborol-1(3H)-ol / 6-[4-(aminomethyl)-2-fluorophenoxy]benzo[c][1,2]oxaborol-1(3H)-ol


Mass: 273.067 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H13BFNO3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 6 / 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: 4.15 Å3/Da / Density % sol: 70.37 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 1.2 M sodium citrate and 2 mM DTT, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jul 24, 2009
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.79→89.09 Å / Num. all: 37670 / Num. obs: 36050 / % possible obs: 95.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.5 % / Rmerge(I) obs: 0.065 / Net I/σ(I): 6.5
Reflection shellResolution: 2.79→2.98 Å / Redundancy: 2.4 % / Rmerge(I) obs: 1.134 / Mean I/σ(I) obs: 0.7 / % possible all: 96.2

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Processing

Software
NameVersionClassification
HKL-2000data collection
CCP4model building
Cootmodel building
REFMAC5.5.0088refinement
XDSdata reduction
SCALAdata scaling
CCP4phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.79→49.5 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.904 / SU B: 29.109 / SU ML: 0.287 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.489 / ESU R Free: 0.336 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28142 710 2 %RANDOM
Rwork0.22239 ---
all0.22356 37670 --
obs0.22356 33966 96.19 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 87.052 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å20 Å2-0.66 Å2
2--0.27 Å20 Å2
3----0.99 Å2
Refinement stepCycle: LAST / Resolution: 2.79→49.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6292 0 40 6 6338
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0216134
X-RAY DIFFRACTIONr_bond_other_d0.0010.024149
X-RAY DIFFRACTIONr_angle_refined_deg1.1411.9458347
X-RAY DIFFRACTIONr_angle_other_deg0.82439854
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2085772
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.63124.088296
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.79315882
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.8621534
X-RAY DIFFRACTIONr_chiral_restr0.0650.2881
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0217086
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021334
X-RAY DIFFRACTIONr_mcbond_it1.40323866
X-RAY DIFFRACTIONr_mcbond_other0.25421562
X-RAY DIFFRACTIONr_mcangle_it2.60236148
X-RAY DIFFRACTIONr_scbond_it3.7442268
X-RAY DIFFRACTIONr_scangle_it5.90162199
LS refinement shellResolution: 2.79→2.862 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.533 39 -
Rwork0.52 2232 -
obs--100 %
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)
14.96312.3205-0.70012.1251-0.44892.6586-0.23780.20160.141-0.29330.1254-0.1155-0.1248-0.06170.11240.17570.0410.09360.03720.00940.250612.0670.556-38.763
26.0028-2.20431.17342.1855-0.36692.4412-0.2029-0.1632-0.38350.11770.1596-0.32250.2208-0.00380.04320.2566-0.0723-0.08550.05010.02150.443812.292-34.468-35.886
33.50660.1216-0.1442.8313-0.20254.9823-0.0002-0.39730.15580.4679-0.07580.4417-0.2859-1.04440.07590.20370.1690.19770.47880.01760.3717-10.485-1.307-15.323
43.01590.85491.39084.63030.35494.6274-0.080.2621-0.1341-0.97420.16880.2286-0.0076-0.4852-0.08890.4603-0.2204-0.20510.33390.07050.4129-10.724-32.797-59.005
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A27 - 173
2X-RAY DIFFRACTION2B27 - 173
3X-RAY DIFFRACTION3A174 - 373
4X-RAY DIFFRACTION4B174 - 373

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