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- PDB-8x92: Crystal structure of ROCK2 with GNS-2666 inhibitor -

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Basic information

Entry
Database: PDB / ID: 8x92
TitleCrystal structure of ROCK2 with GNS-2666 inhibitor
ComponentsRho-associated protein kinase 2
KeywordsTRANSFERASE/INHIBITOR / Inhibitor / 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 centrosome duplication / regulation of angiotensin-activated signaling pathway / negative regulation of protein localization to lysosome / regulation of keratinocyte differentiation / positive regulation of connective tissue replacement / positive regulation of fibroblast growth factor production / response to transforming growth factor beta / positive regulation of amyloid precursor protein catabolic process ...positive regulation of connective tissue growth factor production / cellular response to acetylcholine / positive regulation of centrosome duplication / regulation of angiotensin-activated signaling pathway / negative regulation of protein localization to lysosome / regulation of keratinocyte differentiation / positive regulation of connective tissue replacement / positive regulation of fibroblast growth factor production / response to transforming growth factor beta / positive regulation of amyloid precursor protein catabolic process / regulation of cell junction assembly / negative regulation of bicellular tight junction assembly / regulation of nervous system process / positive regulation of protein localization to early endosome / regulation of cellular response to hypoxia / modulation by host of viral process / negative regulation of nitric oxide biosynthetic process / embryonic morphogenesis / negative regulation of biomineral tissue development / regulation of cell motility / cellular response to testosterone stimulus / regulation of establishment of endothelial barrier / RHO GTPases Activate ROCKs / regulation of stress fiber assembly / actomyosin structure organization / Sema4D induced cell migration and growth-cone collapse / response to angiotensin / aortic valve morphogenesis / cortical actin cytoskeleton organization / RHOBTB1 GTPase cycle / regulation of establishment of cell polarity / tau-protein kinase activity / regulation of focal adhesion assembly / positive regulation of amyloid-beta formation / RHOB GTPase cycle / EPHA-mediated growth cone collapse / RHOC GTPase cycle / positive regulation of cardiac muscle hypertrophy / mRNA destabilization / mitotic cytokinesis / centrosome duplication / RHOH GTPase cycle / smooth muscle contraction / RHOA GTPase cycle / endopeptidase activator activity / epithelial to mesenchymal transition / Rho protein signal transduction / regulation of cell adhesion / 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 / tau protein binding / VEGFA-VEGFR2 Pathway / cytoplasmic ribonucleoprotein granule / rhythmic process / G alpha (12/13) signalling events / positive regulation of protein phosphorylation / actin cytoskeleton organization / protease binding / Potential therapeutics for SARS / eukaryotic translation initiation factor 2alpha kinase activity / cytoskeleton / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / positive regulation of cell migration / 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 / zinc ion binding
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. ...: / 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 / 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
: / Rho-associated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsPark, T.H. / Bong, S.M. / Lee, S.J. / Lee, B.I.
Funding support Korea, Republic Of, 1items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)NRF-2023R1A2C1002654 Korea, Republic Of
CitationJournal: To Be Published
Title: crystal structure of rock2 with GNS-2666 inhibitor
Authors: Park, T.H. / Lee, B.I.
History
DepositionNov 29, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 4, 2024Provider: repository / Type: Initial release

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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)90,8975
Polymers90,0562
Non-polymers8413
Water1,44180
1
A: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,4973
Polymers45,0281
Non-polymers4682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,4012
Polymers45,0281
Non-polymers3721
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)53.727, 136.467, 148.574
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 45028.246 Da / Num. of mol.: 2
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-YEW / ~{N}-methyl-3-[[6-(2-methylpyrazol-3-yl)-1-oxidanylidene-isoquinolin-2-yl]methyl]benzamide


Mass: 372.420 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H20N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 80 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 3.02 Å3/Da / Density % sol: 59.33 %
Crystal growTemperature: 287 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 2.5 M Ammonium sulfate, 0.1 M Bis-tris (pH5.5)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL44XU / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 11, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 106703 / % possible obs: 99.5 % / Redundancy: 3.52 % / CC1/2: 0.998 / Rmerge(I) obs: 0.055 / Rrim(I) all: 0.064 / Net I/σ(I): 11.39
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rrim(I) allDiffraction-ID
2.2-2.331.238169590.4251.4731
2.33-2.490.74162210.7040.8771
2.49-2.690.427152260.8830.51
2.69-2.950.215139110.9650.2521
2.95-3.290.102125800.9890.1211
3.29-3.80.056111410.9950.0671
3.8-4.650.04293550.9970.0491
4.65-6.540.03772610.9970.0441
6.54-500.03140490.9980.0371

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Processing

Software
NameVersionClassification
PHENIXv1.21refinement
XDSdata scaling
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4L6Q

4l6q


Resolution: 2.2→47.382 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflection
Rfree0.2397 3810 3.57 %
Rwork0.2089 --
obs-106662 99.42 %
Displacement parametersBiso mean: 71.3 Å2
Refinement stepCycle: LAST / Resolution: 2.2→47.382 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5971 0 5 80 6056
LS refinement shellResolution: 2.2→2.278 Å
RfactorNum. reflection% reflection
Rfree0.3695 -3.57 %
Rwork0.3507 5361 -
obs--96.91 %

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