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- PDB-9ep8: Crystal structure of ROCK2 in complex with a 8-(azaindolyl)-benzo... -

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Basic information

Entry
Database: PDB / ID: 9ep8
TitleCrystal structure of ROCK2 in complex with a 8-(azaindolyl)-benzoazepinone inhibitor
ComponentsRho-associated protein kinase 2
KeywordsTRANSFERASE / ROCK2 / kinase inhibitor / 8-(azaindolyl)-benzoazepinone
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: 2.63 Å
AuthorsPala, D. / Clark, D. / Pioselli, B. / Accetta, A. / Rancati, F.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Rsc Med Chem / Year: 2024
Title: Design and synthesis of novel 8-(azaindolyl)-benzoazepinones as potent and selective ROCK inhibitors.
Authors: Pala, D. / Clark, D. / Edwards, C. / Pasqua, E. / Tigli, L. / Pioselli, B. / Malysa, P. / Facchinetti, F. / Rancati, F. / Accetta, A.
History
DepositionMar 18, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 25, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2024Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Nov 27, 2024Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _pdbx_entry_details.has_protein_modification

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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)185,0769
Polymers183,6014
Non-polymers1,4765
Water1,42379
1
A: Rho-associated protein kinase 2
B: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,5074
Polymers91,8002
Non-polymers7072
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3720 Å2
ΔGint-27 kcal/mol
Surface area36260 Å2
MethodPISA
2
C: Rho-associated protein kinase 2
D: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,5695
Polymers91,8002
Non-polymers7693
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4030 Å2
ΔGint-25 kcal/mol
Surface area35960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)151.409, 134.292, 93.548
Angle α, β, γ (deg.)90.00, 109.71, 90.00
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
22
33
44
55
66
/ NCS ensembles :
ID
1
2
3
4
5
6

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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: 45900.125 Da / Num. of mol.: 4
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-A1H6L / 8-(azaindolyl)-benzoazepinone / 3-phenyl-7-(1~{H}-pyrrolo[2,3-b]pyridin-4-yl)-2,5-dihydro-1~{H}-3-benzazepin-4-one


Mass: 353.416 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H19N3O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 79 / 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: 2.44 Å3/Da / Density % sol: 49.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: PEG6000, LiCl, MES/NaOH

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99989 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 22, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99989 Å / Relative weight: 1
ReflectionResolution: 2.63→97.75 Å / Num. obs: 50205 / % possible obs: 95.8 % / Redundancy: 2 % / Rmerge(I) obs: 0.036 / Net I/σ(I): 14.06
Reflection shellResolution: 2.63→2.88 Å / Rmerge(I) obs: 0.439 / Num. unique obs: 12069

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.8.0155refinement
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.63→97.74 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.942 / SU B: 33.803 / SU ML: 0.321 / Cross valid method: THROUGHOUT / ESU R: 3.107 / ESU R Free: 0.323 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2418 851 1.7 %RANDOM
Rwork0.20245 ---
obs0.20312 49354 95.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 88.116 Å2
Baniso -1Baniso -2Baniso -3
1--1.99 Å2-0 Å2-1.65 Å2
2---0.18 Å20 Å2
3---2.67 Å2
Refinement stepCycle: LAST / Resolution: 2.63→97.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12379 0 112 79 12570
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01912479
X-RAY DIFFRACTIONr_bond_other_d0.0030.0211535
X-RAY DIFFRACTIONr_angle_refined_deg1.6151.9616930
X-RAY DIFFRACTIONr_angle_other_deg1.259326403
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.72351508
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.42524.007599
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.079151990
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.631571
X-RAY DIFFRACTIONr_chiral_restr0.0930.21807
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02114214
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022995
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_it6.5626.596074
X-RAY DIFFRACTIONr_mcbond_other6.566.5896073
X-RAY DIFFRACTIONr_mcangle_it9.12711.1197565
X-RAY DIFFRACTIONr_mcangle_other9.12611.1217566
X-RAY DIFFRACTIONr_scbond_it6.8687.0026405
X-RAY DIFFRACTIONr_scbond_other6.8687.0026405
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other9.61211.5989365
X-RAY DIFFRACTIONr_long_range_B_refined11.53958.39213504
X-RAY DIFFRACTIONr_long_range_B_other11.53858.38613502
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A88360.02
12B88360.02
21A90820.02
22C90820.02
31A92700.03
32D92700.03
41B88600.02
42C88600.02
51B89360.02
52D89360.02
61C91380.02
62D91380.02
LS refinement shellResolution: 2.63→2.698 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.604 52 -
Rwork0.43 3677 -
obs--96.53 %
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)
15.83770.67252.05730.7971.66373.7544-0.29760.26010.1479-0.17430.1448-0.026-0.23320.20340.15280.24450.030.09530.4479-0.08090.305650.4817.83819.339
22.89862.0857-0.02443.14590.14484.0282-0.1161-0.03370.3625-0.03860.0354-0.2225-0.32510.11010.08060.08180.1221-0.02890.34370.00620.193628.6224.44316.173
34.6751-0.5129-0.45172.7425-0.42372.63330.0434-0.61180.37940.6133-0.1043-0.1452-0.10290.03740.0610.16580.0389-0.01720.4786-0.02810.03819.69-3.24130.899
43.24351.60380.8342.12161.06861.3601-0.17430.32670.3354-0.10.1937-0.2161-0.1192-0.0305-0.01930.13730.08420.0050.45040.00860.159924.2950.75516.914
56.0643-0.75651.70151.6174-1.68361.9677-0.1856-0.3047-0.2245-0.03630.18720.0630.1072-0.1401-0.00160.25280.06170.13560.4091-0.04290.318551.3975.69526.889
66.1477-0.3171-0.37113.5072-0.64873.2485-0.2591-0.11040.43090.19460.01620.0695-0.2741-0.02590.24290.1074-0.0105-0.00890.4128-0.04990.073673.6645.67729.019
74.22370.5877-1.31364.2107-0.64864.1821-0.01680.50670.9362-0.4391-0.0677-0.4229-0.68860.24380.08440.2565-0.07790.07510.67850.07350.427993.80810.65713.988
84.3707-1.5910.3392.68470.01050.1543-0.1653-0.16170.26160.02270.0679-0.0859-0.06050.02010.09740.19-0.01990.070.49830.02070.13778.9573.90226.631
93.32881.62581.39231.4069-0.05662.2923-0.27820.4078-0.0476-0.06250.2363-0.0456-0.81560.08760.04180.49220.0267-0.00320.5037-0.07730.1196-18.92839.9147.678
104.43550.90960.92492.29920.374.5802-0.09090.3218-0.6057-0.10010.1684-0.1647-0.17770.0936-0.07760.09050.02810.05680.4731-0.07890.116-0.08839.83819.748
112.9711-0.26890.67245.0566-0.91944.05550.111-0.3676-0.66470.66080.0422-0.13980.2707-0.109-0.15330.320.036-0.01660.56180.00220.18097.0633.78943.648
123.48081.76111.94452.48841.25311.2748-0.08150.371-0.26370.05770.2079-0.1425-0.16450.2626-0.12640.28760.04530.04850.565-0.04010.05942.63241.27224.622
136.8122-1.63071.06310.68540.52232.4753-0.2191-0.1553-0.21550.08370.14660.1111-0.23180.16080.07250.32740.08450.05840.3278-0.07540.146-24.25237.08213.03
144.0735-1.5829-0.44913.7859-1.21833.1897-0.06690.1797-0.40150.0427-0.0032-0.31430.1520.19020.070.04040.0093-0.0120.3932-0.0910.1292-43.71340.3372.408
152.22550.20641.02552.8072-0.09523.65620.05410.4293-0.2829-0.40270.0873-0.58120.10670.5438-0.14150.15380.0150.07510.6807-0.0710.1472-50.43249.871-20.185
165.3085-2.13871.46260.9134-0.74361.4637-0.14280.0705-0.22550.10510.07890.0408-0.1131-0.11310.06390.18970.00820.00820.4606-0.11140.0991-47.13244.097-0.591
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A22 - 91
2X-RAY DIFFRACTION2A92 - 170
3X-RAY DIFFRACTION3A171 - 355
4X-RAY DIFFRACTION4A356 - 417
5X-RAY DIFFRACTION5B24 - 91
6X-RAY DIFFRACTION6B92 - 170
7X-RAY DIFFRACTION7B171 - 355
8X-RAY DIFFRACTION8B356 - 417
9X-RAY DIFFRACTION9C24 - 91
10X-RAY DIFFRACTION10C92 - 170
11X-RAY DIFFRACTION11C171 - 355
12X-RAY DIFFRACTION12C356 - 417
13X-RAY DIFFRACTION13D22 - 91
14X-RAY DIFFRACTION14D92 - 170
15X-RAY DIFFRACTION15D171 - 355
16X-RAY DIFFRACTION16D356 - 417

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