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- PDB-5xvf: Crystal Structure of PAK4 in complex with inhibitor CZH062 -

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Basic information

Entry
Database: PDB / ID: 5xvf
TitleCrystal Structure of PAK4 in complex with inhibitor CZH062
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 / regulation of MAPK cascade / RHOH GTPase cycle / CDC42 GTPase cycle / RHOU GTPase cycle ...dendritic spine development / cadherin binding involved in cell-cell adhesion / Activation of RAC1 / RHOV GTPase cycle / RHOJ GTPase cycle / RHOQ GTPase cycle / regulation of MAPK cascade / RHOH GTPase cycle / CDC42 GTPase cycle / RHOU GTPase cycle / cellular response to organic cyclic compound / RHOG GTPase cycle / RAC2 GTPase cycle / RAC3 GTPase cycle / negative regulation of endothelial cell apoptotic process / cytoskeleton organization / RAC1 GTPase cycle / regulation of cell growth / adherens junction / positive regulation of angiogenesis / cell migration / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / cell cycle / phosphorylation / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 ...p21 activated kinase binding domain / CRIB domain superfamily / P21-Rho-binding domain / CRIB domain profile. / P21-Rho-binding domain / CRIB domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-8FR / Serine/threonine-protein kinase PAK 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.655 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

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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)33,0412
Polymers32,6831
Non-polymers3581
Water1267
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13690 Å2
Unit cell
Length a, b, c (Å)65.404, 65.404, 180.863
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein Serine/threonine-protein kinase PAK 4 / p21-activated kinase 4 / PAK-4


Mass: 32682.955 Da / Num. of mol.: 1 / Fragment: PAK4 Kinase Domain (UNP RESIDUES 300-588)
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-8FR / 2-(4-azanylpiperidin-1-yl)-6-chloranyl-N-(1-methylimidazol-4-yl)quinazolin-4-amine


Mass: 357.841 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20ClN7
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: H2O

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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: 2.96 Å3/Da / Density % sol: 58.47 % / Mosaicity: 0.632 ° / Mosaicity esd: 0.008 °
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 7.5 / Details: 0.1 M HEPES pH 7.5, 25% PEG3350.

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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: Jan 9, 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: 2.65→50 Å / Num. obs: 12074 / % possible obs: 99.9 % / Redundancy: 11 % / Biso Wilson estimate: 65.77 Å2 / Rmerge(I) obs: 0.088 / Rpim(I) all: 0.028 / Rrim(I) all: 0.092 / Χ2: 1.968 / Net I/σ(I): 10.6 / Num. measured all: 132467
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.65-2.7111.0755900.8720.3361.1281.393100
2.7-2.7410.90.855960.870.2670.8921.329100
2.74-2.811.10.685740.9250.2120.7131.338100
2.8-2.8510.90.6555860.90.2060.6871.294100
2.85-2.92110.5785810.9470.1810.6061.348100
2.92-2.9811.10.4775950.9640.1490.51.364100
2.98-3.0611.10.3685820.9680.1150.3861.385100
3.06-3.1411.10.2935870.980.0910.3071.477100
3.14-3.2311.30.2285910.990.0710.2391.48100
3.23-3.3411.20.1865900.9920.0580.1951.67100
3.34-3.4611.20.1596030.9940.0490.1661.763100
3.46-3.611.20.1235910.9970.0380.1292.035100
3.6-3.76110.1036000.9960.0320.1082.486100
3.76-3.9610.90.0895970.9970.0280.0932.854100
3.96-4.2110.60.0846100.9970.0270.0893.413100
4.21-4.5310.50.0696010.9990.0230.0733.69999.8
4.53-4.99110.0696190.9980.0220.0733.337100
4.99-5.7110.80.0566260.9980.0180.0592.139100
5.71-7.1911.50.0476530.9990.0140.0491.87100
7.19-5010.30.0327020.9990.0110.0341.71898.5

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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: 2.655→37.193 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 27.46 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2514 605 5.04 %
Rwork0.1935 11398 -
obs0.1965 12003 99.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 146.61 Å2 / Biso mean: 74.48 Å2 / Biso min: 30 Å2
Refinement stepCycle: final / Resolution: 2.655→37.193 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2290 0 25 7 2322
Biso mean--65.72 66.26 -
Num. residues----290
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092364
X-RAY DIFFRACTIONf_angle_d1.0443206
X-RAY DIFFRACTIONf_chiral_restr0.055360
X-RAY DIFFRACTIONf_plane_restr0.007410
X-RAY DIFFRACTIONf_dihedral_angle_d19.0631447
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 4

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.6546-2.92170.33171440.23362754289899
2.9217-3.34420.29351460.219427992945100
3.3442-4.21240.25691570.197528382995100
4.2124-37.19670.22441580.17830073165100
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)
10.91310.9369-0.47863.00251.91991.6762-0.0609-0.00950.05550.3049-0.0347-0.4271-0.13740.0401-0.00010.56210.079-0.05020.3072-0.0230.471783.803938.1367203.2736
22.19081.67893.09480.79050.47711.75060.08950.0284-0.05910.1254-0.0613-0.060.2239-0.2052-0.00250.42610.08890.01060.3316-0.08530.397970.801433.8379192.854
32.13271.22372.2050.99550.07731.3397-0.5750.86270.2237-0.03270.17090.2066-0.51480.6848-0.0350.5299-0.1143-0.18220.57580.03130.452874.727441.8684177.9193
41.69121.70511.55250.8950.86141.5457-0.43620.1140.17740.0323-0.0736-0.356-0.4823-0.5237-0.04270.55560.169-0.18990.5104-0.0090.596961.603535.0757179.8942
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 299 through 372 )A299 - 372
2X-RAY DIFFRACTION2chain 'A' and (resid 373 through 453 )A373 - 453
3X-RAY DIFFRACTION3chain 'A' and (resid 454 through 542 )A454 - 542
4X-RAY DIFFRACTION4chain 'A' and (resid 543 through 588 )A543 - 588

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