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- PDB-5xvg: Crystal Structure of PAK4 in complex with inhibitor CZH226 -

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Basic information

Entry
Database: PDB / ID: 5xvg
TitleCrystal Structure of PAK4 in complex with inhibitor CZH226
ComponentsSerine/threonine-protein kinase PAK 4
KeywordsTRANSFERASE / ATP binding pocket
Function / homology
Function and homology information


dendritic spine development / cadherin binding involved in cell-cell adhesion / Activation of RAC1 / RHOV GTPase cycle / RHOJ GTPase cycle / RHOQ GTPase cycle / RHOU GTPase cycle / regulation of MAPK cascade / CDC42 GTPase cycle / RHOH GTPase cycle ...dendritic spine development / cadherin binding involved in cell-cell adhesion / Activation of RAC1 / RHOV GTPase cycle / RHOJ GTPase cycle / RHOQ GTPase cycle / RHOU GTPase cycle / regulation of MAPK cascade / CDC42 GTPase cycle / RHOH GTPase cycle / RHOG GTPase cycle / RAC2 GTPase cycle / RAC3 GTPase cycle / negative regulation of endothelial cell apoptotic process / RAC1 GTPase cycle / cytoskeleton organization / cellular response to starvation / adherens junction / regulation of cell growth / positive regulation of angiogenesis / cell migration / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / apoptotic process / Golgi apparatus / signal transduction / ATP binding / cytosol / cytoplasm
Similarity search - Function
p21 activated kinase binding domain / : / CRIB domain superfamily / P21-Rho-binding domain / CRIB domain profile. / P21-Rho-binding domain / CRIB domain / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 ...p21 activated kinase binding domain / : / CRIB domain superfamily / P21-Rho-binding domain / CRIB domain profile. / P21-Rho-binding domain / CRIB domain / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase 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-8FX / ETHANOL / Serine/threonine-protein kinase PAK 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsZhao, F. / Li, H.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Structure-Based Design of 6-Chloro-4-aminoquinazoline-2-carboxamide Derivatives as Potent and Selective p21-Activated Kinase 4 (PAK4) Inhibitors.
Authors: Hao, C. / Zhao, F. / Song, H. / Guo, J. / Li, X. / Jiang, X. / Huan, R. / Song, S. / Zhang, Q. / Wang, R. / Wang, K. / Pang, Y. / Liu, T. / Lu, T. / Huang, W. / Wang, J. / Lin, B. / He, Z. / ...Authors: Hao, C. / Zhao, F. / Song, H. / Guo, J. / Li, X. / Jiang, X. / Huan, R. / Song, S. / Zhang, Q. / Wang, R. / Wang, K. / Pang, Y. / Liu, T. / Lu, T. / Huang, W. / Wang, J. / Lin, B. / He, Z. / Li, H. / Li, F. / Zhao, D. / Cheng, M.
History
DepositionJun 27, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 7, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase PAK 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,92710
Polymers33,0981
Non-polymers8289
Water1,74797
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1400 Å2
ΔGint23 kcal/mol
Surface area13500 Å2
Unit cell
Length a, b, c (Å)42.169, 64.914, 99.279
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 Serine/threonine-protein kinase PAK 4 / p21-activated kinase 4 / PAK-4


Mass: 33098.449 Da / Num. of mol.: 1 / Fragment: PAK4 Kinase Domain (UNP RESIDUES 300-591)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PAK4, KIAA1142 / Plasmid: pSUMOH10 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: O96013, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-8FX / [6-chloranyl-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl]-[(3R)-3-methylpiperazin-1-yl]methanone


Mass: 411.888 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22ClN7O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EOH / ETHANOL


Mass: 46.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 97 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.05 Å3/Da / Density % sol: 40.08 % / Mosaicity: 20.715 ° / Mosaicity esd: 5.566 °
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 7.5
Details: 0.1 M HEPES pH 7.5, 0.5M Magnesium formate dihydrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 1.2818 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 31, 2016 / Details: mirrors
RadiationMonochromator: double crystal, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.2818 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 16543 / % possible obs: 99.9 % / Redundancy: 5.8 % / Biso Wilson estimate: 31.16 Å2 / Rmerge(I) obs: 0.108 / Rpim(I) all: 0.049 / Rrim(I) all: 0.119 / Χ2: 1.624 / Net I/σ(I): 7.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.1-2.145.90.7240.8010.3220.7941.169100
2.14-2.185.90.6020.8730.2670.6591.247100
2.18-2.225.90.570.8430.2530.6241.219100
2.22-2.265.90.5090.8820.2260.5581.288100
2.26-2.315.90.4510.9210.2010.4941.261100
2.31-2.375.90.3890.910.1740.4271.297100
2.37-2.425.90.3520.9410.1570.3861.339100
2.42-2.495.90.3390.9460.1510.3711.399.9
2.49-2.5660.2730.950.1210.2991.364100
2.56-2.655.90.2670.9560.120.2931.438100
2.65-2.7460.2190.9690.0970.241.394100
2.74-2.855.90.1770.9840.0790.1941.40399.9
2.85-2.985.90.1550.9860.070.1711.473100
2.98-3.145.90.1220.990.0540.1341.535100
3.14-3.335.90.1020.9930.0460.1121.80199.9
3.33-3.595.80.0890.9930.040.0982.32899.9
3.59-3.955.60.0730.9960.0340.082.6899.9
3.95-4.525.60.0620.9970.0280.0682.953100
4.52-5.75.50.0510.9970.0240.0571.93399.7
5.7-505.40.050.9970.0240.0552.12299.9

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Processing

Software
NameVersionClassification
PHENIXdev_2689refinement
DENZOdata collection
HKL-2000data scaling
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2J0I

2j0i


Resolution: 2.1→39.432 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 23.93
RfactorNum. reflection% reflection
Rfree0.2354 859 5.21 %
Rwork0.1815 --
obs0.1843 16494 99.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 73.49 Å2 / Biso mean: 33.4953 Å2 / Biso min: 18.75 Å2
Refinement stepCycle: final / Resolution: 2.1→39.432 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2320 0 56 97 2473
Biso mean--34.57 39.61 -
Num. residues----293
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072420
X-RAY DIFFRACTIONf_angle_d0.8753268
X-RAY DIFFRACTIONf_chiral_restr0.052365
X-RAY DIFFRACTIONf_plane_restr0.005417
X-RAY DIFFRACTIONf_dihedral_angle_d16.9571472
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 6

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0998-2.23130.27451500.20752516266699
2.2313-2.40360.22591400.183225642704100
2.4036-2.64540.24581310.176525892720100
2.6454-3.02810.25251450.182825952740100
3.0281-3.81460.24041490.180726172766100
3.8146-39.43860.21681440.178127542898100

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