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- PDB-4o0x: Back pocket flexibility provides group-II PAK selectivity for typ... -

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Basic information

Entry
Database: PDB / ID: 4o0x
TitleBack pocket flexibility provides group-II PAK selectivity for type 1 kinase inhibitors
ComponentsSerine/threonine-protein kinase PAK 4
Keywordstransferase/transferase inhibitor / PAK4 / transferase-transferase inhibitor complex
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 / RHOG GTPase cycle / cellular response to organic cyclic compound / 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 / 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-2OQ / Serine/threonine-protein kinase PAK 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.483 Å
AuthorsRouge, L. / Tam, C. / Wang, W.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Back Pocket Flexibility Provides Group II p21-Activated Kinase (PAK) Selectivity for Type I 1/2 Kinase Inhibitors.
Authors: Staben, S.T. / Feng, J.A. / Lyle, K. / Belvin, M. / Boggs, J. / Burch, J.D. / Chua, C.C. / Cui, H. / Dipasquale, A.G. / Friedman, L.S. / Heise, C. / Koeppen, H. / Kotey, A. / Mintzer, R. / ...Authors: Staben, S.T. / Feng, J.A. / Lyle, K. / Belvin, M. / Boggs, J. / Burch, J.D. / Chua, C.C. / Cui, H. / Dipasquale, A.G. / Friedman, L.S. / Heise, C. / Koeppen, H. / Kotey, A. / Mintzer, R. / Oh, A. / Roberts, D.A. / Rouge, L. / Rudolph, J. / Tam, C. / Wang, W. / Xiao, Y. / Young, A. / Zhang, Y. / Hoeflich, K.P.
History
DepositionDec 14, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2014Group: Database references
Revision 1.2Nov 5, 2014Group: Structure summary

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)33,4172
Polymers33,0681
Non-polymers3481
Water97354
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)64.877, 64.877, 184.010
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 33068.422 Da / Num. of mol.: 1 / Fragment: unp residues 300-591
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PAK4, KIAA1142 / Production host: Escherichia coli (E. coli)
References: UniProt: O96013, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-2OQ / 1-{[1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzimidazol-6-yl]ethynyl}cyclohexanol


Mass: 348.402 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H20N6O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 54 / 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: 2.93 Å3/Da / Density % sol: 58.09 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.3
Details: 0.2 M Tri-Potassium citrate and 20% PEG3350 in the reservoir, and drops set up by mixing 1.0 uL of reservoir solution and 1.0 uL of protein, pH 8.3, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.979403 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 17, 2012
RadiationMonochromator: Liquid Nitrogen cooled Dual Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979403 Å / Relative weight: 1
ReflectionResolution: 2.48→50 Å / Num. all: 14703 / Num. obs: 14703 / % possible obs: 100 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 2.483→2.492 Å / % possible all: 100

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
PHENIX(phenix.refine: 1.7.3_928)refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.483→44.513 Å / SU ML: 0.44 / σ(F): 1.37 / Phase error: 26.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2416 646 4.88 %
Rwork0.2035 --
all0.2416 14703 -
obs0.2053 14658 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 29.701 Å2 / ksol: 0.322 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-22.8084 Å20 Å20 Å2
2--22.8084 Å20 Å2
3---10.0339 Å2
Refinement stepCycle: LAST / Resolution: 2.483→44.513 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2299 0 26 54 2379
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042377
X-RAY DIFFRACTIONf_angle_d0.8963224
X-RAY DIFFRACTIONf_dihedral_angle_d13.888903
X-RAY DIFFRACTIONf_chiral_restr0.062360
X-RAY DIFFRACTIONf_plane_restr0.004414
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4834-2.58290.40221310.33332805X-RAY DIFFRACTION100
2.5829-2.70040.36361470.29982818X-RAY DIFFRACTION100
2.7004-2.84270.31791850.27992747X-RAY DIFFRACTION100
2.8427-3.02080.36591440.29962749X-RAY DIFFRACTION100
3.0208-3.2540.2571540.25762826X-RAY DIFFRACTION100
3.254-3.58130.28071290.22922799X-RAY DIFFRACTION100
3.5813-4.09920.25461490.18712798X-RAY DIFFRACTION100
4.0992-5.16340.17281170.1562823X-RAY DIFFRACTION100
5.1634-44.51960.17481360.16022813X-RAY DIFFRACTION100
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)
10.0101-0-0.01440.06860.00690.0524-0.05050.01320.03170.041-0.04540.0102-0.0751-0.0119-0.07870.41580.1049-0.1225-0.0624-0.07590.1749-16.13174.782522.6557
20.04820.03880.01240.07260.00340.0852-0.31530.11930.2517-0.0821-0.0444-0.0044-0.26360.0683-0.42130.28130.0202-0.36320.11350.13290.0439-28.29744.65730.9385
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 299:398 )A299 - 398
2X-RAY DIFFRACTION2( CHAIN A AND RESID 399:589 )A399 - 589

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