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- PDB-7jnt: CRYSTAL STRUCTURE OF RHO-ASSOCIATED PROTEIN KINASE 2 (ROCK2) IN C... -

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Basic information

Entry
Database: PDB / ID: 7jnt
TitleCRYSTAL STRUCTURE OF RHO-ASSOCIATED PROTEIN KINASE 2 (ROCK2) IN COMPLEX WITH A POTENT AND SELECTIVE DUAL ROCK INHIBITOR
ComponentsRho-associated protein kinase 2
KeywordsTRANSFERASE / ROCK 2 / KINASE / TRANSFERASE-TRANSFERASE INHIBIT COMPLEX / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of connective tissue growth factor production / cellular response to acetylcholine / positive regulation of fibroblast growth factor production / positive regulation of centrosome duplication / regulation of angiotensin-activated signaling pathway / negative regulation of protein localization to lysosome / regulation of keratinocyte differentiation / Rho-dependent protein serine/threonine kinase activity / positive regulation of connective tissue replacement / response to transforming growth factor beta ...positive regulation of connective tissue growth factor production / cellular response to acetylcholine / positive regulation of fibroblast growth factor production / positive regulation of centrosome duplication / regulation of angiotensin-activated signaling pathway / negative regulation of protein localization to lysosome / regulation of keratinocyte differentiation / Rho-dependent protein serine/threonine kinase activity / positive regulation of connective tissue replacement / response to transforming growth factor beta / positive regulation of amyloid precursor protein catabolic process / regulation of cell junction assembly / regulation of nervous system process / positive regulation of protein localization to early endosome / host-mediated perturbation of viral process / cellular response to testosterone stimulus / embryonic morphogenesis / regulation of cellular response to hypoxia / negative regulation of nitric oxide biosynthetic process / regulation of cell motility / negative regulation of biomineral tissue development / regulation of establishment of endothelial barrier / response to angiotensin / regulation of stress fiber assembly / RHO GTPases Activate ROCKs / actomyosin structure organization / Sema4D induced cell migration and growth-cone collapse / aortic valve morphogenesis / RHOBTB1 GTPase cycle / cortical actin cytoskeleton organization / regulation of establishment of cell polarity / negative regulation of bicellular tight junction assembly / tau-protein kinase activity / regulation of focal adhesion assembly / RHOB GTPase cycle / positive regulation of amyloid-beta formation / EPHA-mediated growth cone collapse / positive regulation of cardiac muscle hypertrophy / RHOC GTPase cycle / mRNA destabilization / centrosome duplication / mitotic cytokinesis / RHOH GTPase cycle / smooth muscle contraction / epithelial to mesenchymal transition / RHOA GTPase cycle / endopeptidase activator activity / regulation of cell adhesion / Rho protein signal transduction / positive regulation of stress fiber assembly / EPHB-mediated forward signaling / positive regulation of endothelial cell migration / negative regulation of angiogenesis / blood vessel diameter maintenance / response to ischemia / protein localization to plasma membrane / regulation of actin cytoskeleton organization / regulation of circadian rhythm / small GTPase binding / VEGFA-VEGFR2 Pathway / tau protein binding / cytoplasmic ribonucleoprotein granule / positive regulation of protein phosphorylation / rhythmic process / G alpha (12/13) signalling events / actin cytoskeleton organization / protease binding / Potential therapeutics for SARS / cytoskeleton / protein phosphorylation / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / positive regulation of cell migration / 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 / zinc ion binding / ATP binding / nucleus / 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. / MRCK kinase PH domain / : / HR1 rho-binding domain / REM-1 domain profile. ...: / Rho-associated protein kinase 2, HR1 domain / 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 / 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
Similarity search - Domain/homology
Chem-VFA / Rho-associated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.214 Å
AuthorsMuckelbauer, J.K.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2020
Title: Identification of 5H-chromeno[3,4-c]pyridine and 6H-isochromeno[3,4-c]pyridine derivatives as potent and selective dual ROCK inhibitors.
Authors: Hu, Z. / Wang, C. / Sitkoff, D. / Cheadle, N.L. / Xu, S. / Muckelbauer, J.K. / Adam, L.P. / Wexler, R.R. / Quan, M.L.
History
DepositionAug 5, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 2, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 6, 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
C: Rho-associated protein kinase 2
D: Rho-associated protein kinase 2
E: Rho-associated protein kinase 2
F: Rho-associated protein kinase 2
G: Rho-associated protein kinase 2
H: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)369,65625
Polymers365,6078
Non-polymers4,04917
Water4,918273
1
A: Rho-associated protein kinase 2
B: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,3256
Polymers91,4022
Non-polymers9234
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3400 Å2
ΔGint-26 kcal/mol
Surface area32990 Å2
MethodPISA
2
C: Rho-associated protein kinase 2
D: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,3256
Polymers91,4022
Non-polymers9234
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3390 Å2
ΔGint-26 kcal/mol
Surface area33270 Å2
MethodPISA
3
E: Rho-associated protein kinase 2
F: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,5217
Polymers91,4022
Non-polymers1,1195
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3360 Å2
ΔGint-26 kcal/mol
Surface area33590 Å2
MethodPISA
4
G: Rho-associated protein kinase 2
H: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,4856
Polymers91,4022
Non-polymers1,0834
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3390 Å2
ΔGint-25 kcal/mol
Surface area34210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.617, 100.992, 102.888
Angle α, β, γ (deg.)83.11, 73.53, 78.38
Int Tables number1
Space group name H-MP1

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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: 45700.914 Da / Num. of mol.: 8
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-VFA / N-[(3-methoxyphenyl)methyl]-5H-[1]benzopyrano[3,4-c]pyridine-8-carboxamide


Mass: 346.379 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C21H18N2O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 273 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.49 Å3/Da / Density % sol: 50.6 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: NULL

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 1, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.21→98.7 Å / Num. obs: 105798 / % possible obs: 60.1 % / Observed criterion σ(I): 0 / Redundancy: 2.2 % / Biso Wilson estimate: 61.57 Å2 / Rmerge(I) obs: 0.037 / Net I/σ(I): 11.3
Reflection shellResolution: 2.21→2.46 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.546 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 5290 / % possible all: 11.2

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (6-FEB-2020)refinement
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NULL

Resolution: 2.214→98.44 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.915 / SU R Cruickshank DPI: 0.953 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.713 / SU Rfree Blow DPI: 0.299 / SU Rfree Cruickshank DPI: 0.312
RfactorNum. reflection% reflectionSelection details
Rfree0.2488 865 0.82 %RANDOM
Rwork0.2112 ---
obs0.2115 105798 60.1 %-
Displacement parametersBiso mean: 56.75 Å2
Baniso -1Baniso -2Baniso -3
1--0.7978 Å2-0.169 Å20.3416 Å2
2--0.2033 Å2-0.6212 Å2
3---0.5945 Å2
Refine analyzeLuzzati coordinate error obs: 0.37 Å
Refinement stepCycle: LAST / Resolution: 2.214→98.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms23623 0 283 285 24191
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00824751HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.933650HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d8174SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes4590HARMONIC5
X-RAY DIFFRACTIONt_it24751HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.95
X-RAY DIFFRACTIONt_other_torsion17.84
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion3095SEMIHARMONIC5
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_contact17455SEMIHARMONIC4
LS refinement shellResolution: 2.214→2.38 Å
RfactorNum. reflection% reflection
Rfree0.2848 -0.73 %
Rwork0.2238 2443 -
obs--7.18 %

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