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- PDB-5xva: Crystal Structure of PAK4 in complex with inhibitor CZH216 -

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Basic information

Entry
Database: PDB / ID: 5xva
TitleCrystal Structure of PAK4 in complex with inhibitor CZH216
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 / CDC42 GTPase cycle / RHOH 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 / CDC42 GTPase cycle / RHOH 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 / focal adhesion / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / Golgi apparatus / signal transduction / ATP binding / cytoplasm / cytosol
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-8FU / ETHANOL / Serine/threonine-protein kinase PAK 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.847 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)33,6696
Polymers33,0981
Non-polymers5705
Water3,315184
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area830 Å2
ΔGint15 kcal/mol
Surface area13510 Å2
Unit cell
Length a, b, c (Å)42.649, 64.699, 100.000
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-8FU / [6-chloranyl-4-[(5-methyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl]-[(3R)-3-methylpiperazin-1-yl]methanone


Mass: 385.851 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20ClN7O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EOH / ETHANOL


Mass: 46.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 184 / 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: 2.08 Å3/Da / Density % sol: 40.98 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 6.5
Details: 0.1 M Imidazole pH 6.5, 1.0 M sodium acetate trihydrate

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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: 1.84→50 Å / Num. obs: 24399 / % possible obs: 99.9 % / Redundancy: 5.3 % / Biso Wilson estimate: 24.1 Å2 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.046 / Rrim(I) all: 0.106 / Χ2: 1.791 / Net I/σ(I): 9
Reflection shellResolution: 1.85→1.88 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.875 / CC1/2: 0.648 / Rpim(I) all: 0.418 / Rrim(I) all: 0.973 / Χ2: 1.198 / % possible all: 99.9

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Processing

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

2j0i


Resolution: 1.847→39.563 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.87
RfactorNum. reflection% reflection
Rfree0.2092 1184 4.86 %
Rwork0.1679 --
obs0.1699 24343 99.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 80.22 Å2 / Biso mean: 26.904 Å2 / Biso min: 11.17 Å2
Refinement stepCycle: final / Resolution: 1.847→39.563 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2320 0 39 184 2543
Biso mean--26.04 39.34 -
Num. residues----293
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062406
X-RAY DIFFRACTIONf_angle_d0.9163256
X-RAY DIFFRACTIONf_chiral_restr0.058364
X-RAY DIFFRACTIONf_plane_restr0.006417
X-RAY DIFFRACTIONf_dihedral_angle_d17.8321469
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.8475-1.93160.30861400.22982782292298
1.9316-2.03340.19431440.182728773021100
2.0334-2.16080.24261590.170928312990100
2.1608-2.32760.22491610.171728533014100
2.3276-2.56180.21421310.163729063037100
2.5618-2.93240.20081450.163129023047100
2.9324-3.69410.20061410.160729423083100
3.6941-39.57170.19491630.163530663229100
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)
10.27230.1180.05870.14320.2010.3249-0.0926-0.0742-0.03830.08320.0873-0.1795-0.0496-0.05950.00010.21230.0125-0.03520.18-0.00790.17113.3674-2.970327.1975
20.05520.10040.08590.13960.11320.1272-0.0314-0.03360.0209-0.0367-0.0539-0.0366-0.1381-0.13470.00010.2116-0.0148-0.0160.2162-0.02170.17341.38372.848619.3357
30.07150.0280.06190.01780.03720.0623-0.2002-0.45210.24320.0777-0.03630.093-0.0514-0.285-0.00190.1802-0.01960.01090.2606-0.04770.1729-9.75530.551926.7748
40.13980.08430.23830.14320.04710.5770.0377-0.0306-0.08120.0085-0.0219-0.03630.0457-0.0108-00.136-0.00680.00810.1393-0.01460.1622-14.2862-6.353915.0441
50.1671-0.0243-0.13860.0131-0.00240.1396-0.0168-0.22980.12780.293-0.0946-0.0582-0.13130.0082-0.02730.2139-0.0072-0.01820.1828-0.03820.2079-11.64498.973615.2109
60.93410.04670.05890.4613-0.21850.82360.02130.0380.031-0.09950.00840.00980.0174-0.0107-00.1401-0.01250.00250.1301-0.00950.133-16.6629-1.9041.6628
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 299 through 345 )A299 - 345
2X-RAY DIFFRACTION2chain 'A' and (resid 346 through 369 )A346 - 369
3X-RAY DIFFRACTION3chain 'A' and (resid 370 through 387 )A370 - 387
4X-RAY DIFFRACTION4chain 'A' and (resid 388 through 453 )A388 - 453
5X-RAY DIFFRACTION5chain 'A' and (resid 454 through 471 )A454 - 471
6X-RAY DIFFRACTION6chain 'A' and (resid 472 through 591 )A472 - 591

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