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- PDB-6ed6: Crystal structure of Rock2 with a pyridinylbenzamide based inhibitor -

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Basic information

Entry
Database: PDB / ID: 6ed6
TitleCrystal structure of Rock2 with a pyridinylbenzamide based inhibitor
ComponentsRho-associated protein kinase 2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Rock 2 / kinase / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


cellular response to acetylcholine / positive regulation of centrosome duplication / positive regulation of connective tissue growth factor production / positive regulation of amyloid precursor protein catabolic process / regulation of angiotensin-activated signaling pathway / Rho-dependent protein serine/threonine kinase activity / negative regulation of protein localization to lysosome / positive regulation of connective tissue replacement / regulation of keratinocyte differentiation / positive regulation of fibroblast growth factor production ...cellular response to acetylcholine / positive regulation of centrosome duplication / positive regulation of connective tissue growth factor production / positive regulation of amyloid precursor protein catabolic process / regulation of angiotensin-activated signaling pathway / Rho-dependent protein serine/threonine kinase activity / negative regulation of protein localization to lysosome / positive regulation of connective tissue replacement / regulation of keratinocyte differentiation / positive regulation of fibroblast growth factor production / 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 / 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 / regulation of establishment of endothelial barrier / RHO GTPases Activate ROCKs / regulation of stress fiber assembly / regulation of cell motility / actomyosin structure organization / Sema4D induced cell migration and growth-cone collapse / response to angiotensin / aortic valve morphogenesis / regulation of establishment of cell polarity / RHOBTB1 GTPase cycle / cortical actin cytoskeleton organization / regulation of focal adhesion assembly / positive regulation of amyloid-beta formation / RHOB GTPase cycle / tau-protein kinase activity / EPHA-mediated growth cone collapse / mRNA destabilization / positive regulation of cardiac muscle hypertrophy / RHOC GTPase cycle / centrosome duplication / RHOH GTPase cycle / Rho protein signal transduction / mitotic cytokinesis / endopeptidase activator activity / 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 / positive regulation of endothelial cell migration / blood vessel diameter maintenance / negative regulation of angiogenesis / protein localization to plasma membrane / response to ischemia / regulation of actin cytoskeleton organization / tau protein binding / regulation of circadian rhythm / small GTPase binding / VEGFA-VEGFR2 Pathway / cytoplasmic ribonucleoprotein granule / G alpha (12/13) signalling events / rhythmic process / actin cytoskeleton organization / protease binding / 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 / protein phosphorylation / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / positive regulation of gene expression / structural molecule activity / RNA binding / ATP binding / nucleus / metal ion binding / plasma membrane / cytoplasm / cytosol
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-J0P / Rho-associated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.86 Å
AuthorsJudge, R.A. / Hobson, A.D.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Identification of Selective Dual ROCK1 and ROCK2 Inhibitors Using Structure Based Drug Design.
Authors: Hobson, A.D. / Judge, R.A. / Aguirre, A.L. / Brown, B.S. / Cui, Y. / Ding, P. / Dominguez, E. / DiGiammarino, E. / Egan, D.A. / Freiberg, G.M. / Gopalakrishnan, S.M. / Harris, C.M. / Honore, ...Authors: Hobson, A.D. / Judge, R.A. / Aguirre, A.L. / Brown, B.S. / Cui, Y. / Ding, P. / Dominguez, E. / DiGiammarino, E. / Egan, D.A. / Freiberg, G.M. / Gopalakrishnan, S.M. / Harris, C.M. / Honore, M.P. / Kage, K.L. / Kapecki, N.J. / Ling, C. / Ma, J. / Mack, H. / Mamo, M. / Maurus, S. / McRae, B. / Moore, N.S. / Mueller, B.K. / Mueller, R. / Namovic, M.T. / Patel, K. / Pratt, S.D. / Putman, C.B. / Queeney, K.L. / Sarris, K.K. / Schaffter, L.M. / Stoll, V.S. / Vasudevan, A. / Wang, L. / Wang, L. / Wirthl, W. / Yach, K.
History
DepositionAug 8, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 14, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 16, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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 2
B: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,8124
Polymers96,1192
Non-polymers6932
Water1,982110
1
A: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,4062
Polymers48,0591
Non-polymers3461
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,4062
Polymers48,0591
Non-polymers3461
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)53.446, 136.672, 148.691
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 48059.457 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ROCK2, KIAA0619 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: O75116, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-J0P / N-[(2,3-dihydro-1,4-benzodioxin-5-yl)methyl]-4-(pyridin-4-yl)benzamide


Mass: 346.379 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C21H18N2O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 110 / 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: 3.04 Å3/Da / Density % sol: 59.55 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 2.0 M ammonium sulfate, 0.1 M Bis-Tris pH 5.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.9786 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Jun 13, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 2.85→50 Å / Num. obs: 25767 / % possible obs: 99 % / Redundancy: 6.6 % / Biso Wilson estimate: 92.47 Å2 / Rmerge(I) obs: 0.095 / Χ2: 1.47 / Net I/σ(I): 8.8
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.85-2.954.60.61723580.631191.8
2.95-3.075.70.52724880.674199
3.07-3.216.70.41925740.777199.9
3.21-3.387.20.31125530.8651100
3.38-3.597.10.21525901.1381100
3.59-3.877.10.13925631.4021100
3.87-4.2670.09725931.6931100
4.26-4.8770.07726192.1381100
4.87-6.146.90.06326401.8341100
6.14-506.10.0627893.072199.4

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
SCALEPACKdata scaling
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.86→43.4 Å / Cor.coef. Fo:Fc: 0.924 / Cor.coef. Fo:Fc free: 0.908 / SU R Cruickshank DPI: 1.674 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 2.142 / SU Rfree Blow DPI: 0.344 / SU Rfree Cruickshank DPI: 0.347
RfactorNum. reflection% reflectionSelection details
Rfree0.247 1331 5.18 %RANDOM
Rwork0.204 ---
obs0.206 25694 98.9 %-
Displacement parametersBiso max: 179.81 Å2 / Biso mean: 83.87 Å2 / Biso min: 45.84 Å2
Baniso -1Baniso -2Baniso -3
1--4.846 Å20 Å20 Å2
2---14.5506 Å20 Å2
3---19.3965 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: final / Resolution: 2.86→43.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6037 0 52 110 6199
Biso mean--75.38 74.91 -
Num. residues----742
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2180SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1119HARMONIC5
X-RAY DIFFRACTIONt_it6281HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion762SEMIHARMONIC5
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_contact7198SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d6281HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg8516HARMONIC21.14
X-RAY DIFFRACTIONt_omega_torsion2.88
X-RAY DIFFRACTIONt_other_torsion18.57
LS refinement shellResolution: 2.86→2.88 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.1575 23 4.47 %
Rwork0.2424 491 -
all0.2387 514 -
obs--82.82 %

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