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- PDB-4wot: ROCK2 IN COMPLEX WITH 1426382-07-1 -

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Basic information

Entry
Database: PDB / ID: 4wot
TitleROCK2 IN COMPLEX WITH 1426382-07-1
ComponentsRho-associated protein kinase 2
KeywordsTRANSFERASE
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-3SG / Rho-associated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.93 Å
AuthorsAugustin, M. / Krapp, S. / Boland, S. / Defert, O. / Bourin, A. / Alen, J. / Leysen, D.
CitationJournal: J. Med. Chem. / Year: 2015
Title: Design, synthesis, and biological evaluation of novel, highly active soft ROCK inhibitors.
Authors: Boland, S. / Bourin, A. / Alen, J. / Geraets, J. / Schroeders, P. / Castermans, K. / Kindt, N. / Boumans, N. / Panitti, L. / Fransen, S. / Vanormelingen, J. / Stassen, J.M. / Leysen, D. / Defert, O.
History
DepositionOct 16, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0May 6, 2015Provider: repository / Type: Initial release
Revision 1.1Jun 10, 2015Group: Database references
Revision 1.2Apr 25, 2018Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: citation / pdbx_unobs_or_zero_occ_atoms ...citation / pdbx_unobs_or_zero_occ_atoms / refine / reflns / reflns_shell
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.title / _refine.pdbx_method_to_determine_struct / _reflns.pdbx_Rmerge_I_obs / _reflns_shell.Rmerge_I_obs

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)183,9538
Polymers181,8874
Non-polymers2,0664
Water28816
1
A: Rho-associated protein kinase 2
C: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,9764
Polymers90,9432
Non-polymers1,0332
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3830 Å2
ΔGint-27 kcal/mol
Surface area36520 Å2
MethodPISA
2
B: Rho-associated protein kinase 2
D: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,9764
Polymers90,9432
Non-polymers1,0332
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3830 Å2
ΔGint-25 kcal/mol
Surface area36490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)148.192, 148.226, 117.382
Angle α, β, γ (deg.)90.00, 118.65, 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 / coiled-coil-containing ...Rho kinase 2 / Rho-associated / coiled-coil-containing protein kinase 2 / coiled-coil-containing protein kinase II / ROCK-II / p164 ROCK-2


Mass: 45471.727 Da / Num. of mol.: 4 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: O75116, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-3SG / methyl 3-[({2'-(aminomethyl)-5'-[(3-fluoropyridin-4-yl)carbamoyl]biphenyl-3-yl}carbonyl)amino]-4-fluorobenzoate


Mass: 516.495 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C28H22F2N4O4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 16 / 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: 3.17 Å3/Da / Density % sol: 61.28 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: The purified protein was used in crystallisation trials employing both, a standard screen with approximately 1200 different conditions, as well as crystallisation conditions identified using ...Details: The purified protein was used in crystallisation trials employing both, a standard screen with approximately 1200 different conditions, as well as crystallisation conditions identified using literature data. Conditions initially obtained have been optimised using standard strategies, systematically varying parameters critically influencing crystallisation, such as temperature, protein concentration, drop ratio, and others. These conditions were also refined by systematically varying pH or precipitant concentrations. The final selected condition included PEG, at pH 6.5. Crystals were rhombic in shape and grew over a period of one week to the final size

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Mar 23, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
111
211
ReflectionResolution: 2.93→103.01 Å / Num. obs: 47805 / % possible obs: 99.6 % / Observed criterion σ(I): 0 / Redundancy: 4.3 % / Rmerge(I) obs: 0.052
Reflection shellResolution: 2.93→3.18 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.441 / % possible all: 99.7

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.93→103.01 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.886 / SU B: 41.874 / SU ML: 0.366 / Cross valid method: THROUGHOUT / ESU R Free: 0.399 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26806 619 1.3 %RANDOM
Rwork0.22291 ---
obs0.22349 47121 99.86 %-
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: 94.025 Å2
Baniso -1Baniso -2Baniso -3
1--0.08 Å20 Å2-0.03 Å2
2--0.05 Å20 Å2
3---0 Å2
Refinement stepCycle: 1 / Resolution: 2.93→103.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12648 0 152 16 12816
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.02112336
X-RAY DIFFRACTIONr_bond_other_d0.0010.028396
X-RAY DIFFRACTIONr_angle_refined_deg1.1431.95516791
X-RAY DIFFRACTIONr_angle_other_deg1.008319880
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0851554
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.65624.278554
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.166151757
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0141551
X-RAY DIFFRACTIONr_chiral_restr0.0680.21798
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.02114178
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022653
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.08127785
X-RAY DIFFRACTIONr_mcbond_other0.1723153
X-RAY DIFFRACTIONr_mcangle_it2.007312403
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.03144551
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.63364388
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.93→3.006 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.397 40 -
Rwork0.367 3474 -
obs--99.91 %
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)
14.627-1.5052.68040.5584-0.48275.2311-0.1459-0.2052-0.04490.06450.2008-0.0004-0.474-0.123-0.05490.67930.0421-0.05780.2692-0.03870.242528.016-9.00178.378
24.0371-1.47340.69454.0096-1.00256.29770.12990.3254-0.1931-0.01670.18650.0488-0.054-0.244-0.31650.3949-0.0216-0.03010.2215-0.01650.191917.031-8.16459.565
33.1711-0.6468-1.90434.62990.31295.93780.27820.7113-0.2655-0.4307-0.0928-0.3725-0.0226-0.01-0.18530.59430.0536-0.01480.6253-0.09690.321423.868-9.9135.978
42.5761-2.49752.32823.1499-1.64785.54550.2430.2362-0.2036-0.33560.02060.1767-0.1426-0.7005-0.26350.53550.07450.0240.5396-0.03270.290515.839-6.84753.985
54.006-0.13431.90912.36412.48653.7362-0.1580.0094-0.15-0.03330.3372-0.343-0.16070.2765-0.17920.5632-0.0881-0.28710.43580.04181.054532.9427.06973.203
66.82880.37710.4335.02410.51962.3219-0.22680.35080.32490.22440.1797-0.4477-0.350.20070.04720.39560.0218-0.11010.32350.10140.469615.74624.66359.667
75.1295-1.0796-1.33075.24860.08352.4779-0.1212-0.02060.00360.41180.16240.167-0.4058-0.0874-0.04120.37530.0478-0.080.36880.13830.3608-9.21325.72862.349
83.3845-0.34580.88182.93540.91312.1225-0.11050.6592-0.00060.02640.1677-0.3711-0.22360.2077-0.05710.45910.0477-0.05830.39840.09770.46219.62322.15658.054
93.6532-0.17762.81812.3065-2.28514.3484-0.1773-0.0433-0.32870.39770.24450.1706-0.4281-0.3223-0.06720.5342-0.0737-0.24260.41540.03191.131729.89327.52480.048
106.6333-0.4013-0.01135.8153-2.43184.0262-0.2797-0.23550.1304-0.11020.32810.7431-0.3643-0.1668-0.04850.447-0.1041-0.1550.36480.00710.620947.14826.68593.714
113.73990.5891-0.42226.5133-1.21463.0389-0.11110.0011-0.0614-0.4997-0.1866-0.8296-0.15860.67050.29780.4746-0.114-0.04920.59570.01910.682771.79828.37490.804
123.4858-0.28871.94413.3092-2.26693.6372-0.1859-0.7344-0.17530.10760.14680.4134-0.1724-0.08110.0390.553-0.0736-0.08680.5569-0.0180.682953.28624.7895.812
133.92971.4042.31361.3847-0.85724.6656-0.2380.4097-0.1118-0.10950.2467-0.091-0.33260.1961-0.00860.7333-0.0212-0.02760.335-0.0920.281635.399-8.93676.647
143.67880.5648-0.24574.4741-0.48595.773-0.04860.011-0.2939-0.09450.0262-0.08330.02340.34230.02240.38560.0149-0.05870.2501-0.01190.156746.565-6.53695.299
153.29790.0232-1.27174.6806-0.97417.00920.0345-0.1229-0.36170.2644-0.08660.2075-0.0589-0.07180.05210.52020.0498-0.08680.2432-0.01680.186840.418-7.273119.443
161.9281.46112.12291.69480.43175.13380.0620.202-0.21380.18170.0623-0.3368-0.27590.7347-0.12440.5408-0.0231-0.01970.3826-0.05220.348947.449-4.416100.991
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1B1 - 91
2X-RAY DIFFRACTION2B92 - 170
3X-RAY DIFFRACTION3B171 - 355
4X-RAY DIFFRACTION4B356 - 450
5X-RAY DIFFRACTION5A1 - 91
6X-RAY DIFFRACTION6A92 - 170
7X-RAY DIFFRACTION7A171 - 355
8X-RAY DIFFRACTION8A356 - 450
9X-RAY DIFFRACTION9C1 - 91
10X-RAY DIFFRACTION10C92 - 170
11X-RAY DIFFRACTION11C171 - 355
12X-RAY DIFFRACTION12C356 - 450
13X-RAY DIFFRACTION13D1 - 91
14X-RAY DIFFRACTION14D92 - 170
15X-RAY DIFFRACTION15D171 - 355
16X-RAY DIFFRACTION16D356 - 450
17X-RAY DIFFRACTION1B1 - 91
18X-RAY DIFFRACTION2B92 - 170
19X-RAY DIFFRACTION3B171 - 355
20X-RAY DIFFRACTION4B356 - 450
21X-RAY DIFFRACTION5A1 - 91
22X-RAY DIFFRACTION6A92 - 170
23X-RAY DIFFRACTION7A171 - 355
24X-RAY DIFFRACTION8A356 - 450
25X-RAY DIFFRACTION9C1 - 91
26X-RAY DIFFRACTION10C92 - 170
27X-RAY DIFFRACTION11C171 - 355
28X-RAY DIFFRACTION12C356 - 450
29X-RAY DIFFRACTION13D1 - 91
30X-RAY DIFFRACTION14D92 - 170
31X-RAY DIFFRACTION15D171 - 355
32X-RAY DIFFRACTION16D356 - 450

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