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- PDB-7p6n: ROCK2 IN COMPLEX WITH COMPOUND 12 -

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Basic information

Entry
Database: PDB / ID: 7p6n
TitleROCK2 IN COMPLEX WITH COMPOUND 12
ComponentsRho-associated protein kinase 2
KeywordsTRANSFERASE / Rho-associated protein kinase 2 / 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 / regulation of cellular response to hypoxia / embryonic morphogenesis / 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 / RHO GTPases Activate ROCKs / regulation of stress fiber assembly / actomyosin structure organization / Sema4D induced cell migration and growth-cone collapse / aortic valve morphogenesis / cortical actin cytoskeleton organization / RHOBTB1 GTPase cycle / negative regulation of bicellular tight junction assembly / 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 / positive regulation of cardiac muscle hypertrophy / RHOC GTPase cycle / mRNA destabilization / mitotic cytokinesis / centrosome duplication / 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 / tau protein binding / VEGFA-VEGFR2 Pathway / 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 / 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. / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-5YS / Rho-associated protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsMaillard, M.C.
CitationJournal: J.Med.Chem. / Year: 2022
Title: Identification of a Potent, Selective, and Brain-Penetrant Rho Kinase Inhibitor and its Activity in a Mouse Model of Huntington's Disease.
Authors: Ladduwahetty, T. / Lee, M.R. / Maillard, M.C. / Cachope, R. / Todd, D. / Barnes, M. / Beaumont, V. / Chauhan, A. / Gallati, C. / Haughan, A.F. / Kempf, G. / Luckhurst, C.A. / Matthews, K. / ...Authors: Ladduwahetty, T. / Lee, M.R. / Maillard, M.C. / Cachope, R. / Todd, D. / Barnes, M. / Beaumont, V. / Chauhan, A. / Gallati, C. / Haughan, A.F. / Kempf, G. / Luckhurst, C.A. / Matthews, K. / McAllister, G. / Mitchell, P. / Patel, H. / Rose, M. / Saville-Stones, E. / Steinbacher, S. / Stott, A.J. / Thatcher, E. / Tierney, J. / Urbonas, L. / Munoz-Sanjuan, I. / Dominguez, C.
History
DepositionJul 16, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 27, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2023Group: Database references / Refinement description / Category: citation / citation_author / struct_ncs_dom_lim
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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
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)368,32316
Polymers365,6078
Non-polymers2,7158
Water00
1
A: Rho-associated protein kinase 2
hetero molecules

H: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,0814
Polymers91,4022
Non-polymers6792
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_665x+1,y+1,z1
Buried area3840 Å2
ΔGint-24 kcal/mol
Surface area34680 Å2
MethodPISA
2
B: Rho-associated protein kinase 2
hetero molecules

C: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,0814
Polymers91,4022
Non-polymers6792
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_565x,y+1,z1
Buried area3820 Å2
ΔGint-25 kcal/mol
Surface area35560 Å2
MethodPISA
3
D: Rho-associated protein kinase 2
hetero molecules

E: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,0814
Polymers91,4022
Non-polymers6792
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_456x-1,y,z+11
Buried area3870 Å2
ΔGint-24 kcal/mol
Surface area35280 Å2
MethodPISA
4
F: Rho-associated protein kinase 2
hetero molecules

G: Rho-associated protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,0814
Polymers91,4022
Non-polymers6792
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_645x+1,y-1,z1
Buried area3790 Å2
ΔGint-26 kcal/mol
Surface area35330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)95.902, 101.596, 102.755
Angle α, β, γ (deg.)83.920, 73.640, 77.710
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13A
23D
14A
24E
15A
25F
16A
26G
17A
27H
18B
28C
19B
29D
110B
210E
111B
211F
112B
212G
113B
213H
114C
214D
115C
215E
116C
216F
117C
217G
118C
218H
119D
219E
120D
220F
121D
221G
122D
222H
123E
223F
124E
224G
125E
225H
126F
226G
127F
227H
128G
228H

NCS domain segments:

Component-ID: _ / End auth comp-ID: ARG / End label comp-ID: ARG / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11SERSERAA25 - 4177 - 399
21SERSERBB25 - 4177 - 399
12ALAALAAA24 - 4176 - 399
22ALAALACC24 - 4176 - 399
13SERSERAA25 - 4177 - 399
23SERSERDD25 - 4177 - 399
14ALAALAAA24 - 4176 - 399
24ALAALAEE24 - 4176 - 399
15SERSERAA25 - 4177 - 399
25SERSERFF25 - 4177 - 399
16SERSERAA25 - 4177 - 399
26SERSERGG25 - 4177 - 399
17SERSERAA25 - 4177 - 399
27SERSERHH25 - 4177 - 399
18SERSERBB25 - 4177 - 399
28SERSERCC25 - 4177 - 399
19SERSERBB25 - 4177 - 399
29SERSERDD25 - 4177 - 399
110SERSERBB25 - 4177 - 399
210SERSEREE25 - 4177 - 399
111SERSERBB25 - 4177 - 399
211SERSERFF25 - 4177 - 399
112SERSERBB25 - 4177 - 399
212SERSERGG25 - 4177 - 399
113SERSERBB25 - 4177 - 399
213SERSERHH25 - 4177 - 399
114SERSERCC25 - 4177 - 399
214SERSERDD25 - 4177 - 399
115GLYGLYCC23 - 4175 - 399
215GLYGLYEE23 - 4175 - 399
116SERSERCC25 - 4177 - 399
216SERSERFF25 - 4177 - 399
117SERSERCC25 - 4177 - 399
217SERSERGG25 - 4177 - 399
118SERSERCC25 - 4177 - 399
218SERSERHH25 - 4177 - 399
119SERSERDD25 - 4177 - 399
219SERSEREE25 - 4177 - 399
120SERSERDD25 - 4177 - 399
220SERSERFF25 - 4177 - 399
121SERSERDD25 - 4177 - 399
221SERSERGG25 - 4177 - 399
122SERSERDD25 - 4177 - 399
222SERSERHH25 - 4177 - 399
123SERSEREE25 - 4177 - 399
223SERSERFF25 - 4177 - 399
124SERSEREE25 - 4177 - 399
224SERSERGG25 - 4177 - 399
125SERSEREE25 - 4177 - 399
225SERSERHH25 - 4177 - 399
126SERSERFF25 - 4177 - 399
226SERSERGG25 - 4177 - 399
127SERSERFF25 - 4177 - 399
227SERSERHH25 - 4177 - 399
128SERSERGG25 - 4177 - 399
228SERSERHH25 - 4177 - 399

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28

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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 / Fragment: KINASE DOMAIN
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-5YS / ~{N}-[(1~{R})-1-(3-methoxyphenyl)ethyl]-4-pyridin-4-yl-piperidine-1-carboxamide


Mass: 339.431 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C20H25N3O2 / Feature type: SUBJECT OF INVESTIGATION
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: 2.64 Å3/Da / Density % sol: 53.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.25 / 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: 0.99998 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 31, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99998 Å / Relative weight: 1
ReflectionResolution: 3→99.15 Å / Num. obs: 68934 / % possible obs: 94.7 % / Redundancy: 1.7 % / Biso Wilson estimate: 76.282 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.068 / Rrim(I) all: 0.096 / Χ2: 0.937 / Net I/σ(I): 9.7
Reflection shellResolution: 3→3.25 Å / Redundancy: 1.6 % / Rmerge(I) obs: 0.71 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 236 / CC1/2: 0.999 / Rrim(I) all: 0.019 / % possible all: 93.7

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0155refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 3→99.15 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.898 / SU B: 31.931 / SU ML: 0.51 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.533 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2879 513 0.7 %RANDOM
Rwork0.1853 ---
obs0.1859 68421 94.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 500 Å2 / Biso mean: 94.261 Å2 / Biso min: 27.05 Å2
Baniso -1Baniso -2Baniso -3
1-2.6 Å21.09 Å21.22 Å2
2---0.11 Å2-4.55 Å2
3----1.04 Å2
Refinement stepCycle: final / Resolution: 3→99.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms24853 0 200 0 25053
Biso mean--72.59 --
Num. residues----3052
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.01925680
X-RAY DIFFRACTIONr_bond_other_d0.0030.0224191
X-RAY DIFFRACTIONr_angle_refined_deg1.9071.96134662
X-RAY DIFFRACTIONr_angle_other_deg1.369355678
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.78853025
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.97923.9861287
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.90615.0364486
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.52415160
X-RAY DIFFRACTIONr_chiral_restr0.1130.23654
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02128811
X-RAY DIFFRACTIONr_gen_planes_other0.0030.026107
Refine LS restraints NCS

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

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A244820.06
12B244820.06
21A243340.07
22C243340.07
31A246220.06
32D246220.06
41A246720.06
42E246720.06
51A245220.06
52F245220.06
61A245340.07
62G245340.07
71A236500.07
72H236500.07
81B241380.07
82C241380.07
91B245540.06
92D245540.06
101B243480.07
102E243480.07
111B244900.05
112F244900.05
121B244740.07
122G244740.07
131B236540.06
132H236540.06
141C242840.07
142D242840.07
151C242960.07
152E242960.07
161C242360.07
162F242360.07
171C242460.07
172G242460.07
181C234740.07
182H234740.07
191D244580.06
192E244580.06
201D249680.05
202F249680.05
211D245320.07
212G245320.07
221D237440.06
222H237440.06
231E243620.06
232F243620.06
241E246340.07
242G246340.07
251E235580.07
252H235580.07
261F244800.06
262G244800.06
271F236800.06
272H236800.06
281G237060.06
282H237060.06
LS refinement shellResolution: 3→3.078 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.452 34 -
Rwork0.425 4944 -
all-4978 -
obs--92.67 %

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