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- PDB-5dfp: Crystal structure of PAK1 in complex with an inhibitor compound F... -

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Basic information

Entry
Database: PDB / ID: 5dfp
TitleCrystal structure of PAK1 in complex with an inhibitor compound FRAX1036
ComponentsSerine/threonine-protein kinase PAK 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / transferase-transferase inhibitor complex
Function / homology
Function and homology information


negative regulation of cell proliferation involved in contact inhibition / protein localization to cytoplasmic stress granule / positive regulation of microtubule nucleation / hepatocyte growth factor receptor signaling pathway / RHO GTPases Activate ROCKs / gamma-tubulin binding / Activation of RAC1 / CD28 dependent Vav1 pathway / Ephrin signaling / positive regulation of intracellular estrogen receptor signaling pathway ...negative regulation of cell proliferation involved in contact inhibition / protein localization to cytoplasmic stress granule / positive regulation of microtubule nucleation / hepatocyte growth factor receptor signaling pathway / RHO GTPases Activate ROCKs / gamma-tubulin binding / Activation of RAC1 / CD28 dependent Vav1 pathway / Ephrin signaling / positive regulation of intracellular estrogen receptor signaling pathway / DSCAM interactions / RHOV GTPase cycle / regulation of axonogenesis / branching morphogenesis of an epithelial tube / Fc-gamma receptor signaling pathway involved in phagocytosis / RHOJ GTPase cycle / RHOQ GTPase cycle / exocytosis / RHO GTPases activate PAKs / stimulatory C-type lectin receptor signaling pathway / regulation of MAPK cascade / RHOH GTPase cycle / CDC42 GTPase cycle / RHOU GTPase cycle / Sema3A PAK dependent Axon repulsion / Generation of second messenger molecules / intercalated disc / Smooth Muscle Contraction / RAC3 GTPase cycle / RAC2 GTPase cycle / ephrin receptor signaling pathway / localization / positive regulation of microtubule polymerization / RHO GTPases activate PKNs / positive regulation of JUN kinase activity / positive regulation of stress fiber assembly / ruffle / RAC1 GTPase cycle / EPHB-mediated forward signaling / collagen binding / CD209 (DC-SIGN) signaling / neuron projection morphogenesis / VEGFR2 mediated vascular permeability / Signal transduction by L1 / actin filament / regulation of actin cytoskeleton organization / FCERI mediated MAPK activation / MAPK6/MAPK4 signaling / wound healing / G beta:gamma signalling through CDC42 / Regulation of actin dynamics for phagocytic cup formation / ruffle membrane / Z disc / cell-cell junction / cell migration / lamellipodium / positive regulation of peptidyl-serine phosphorylation / chromosome / actin cytoskeleton organization / nuclear membrane / protein autophosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / positive regulation of cell migration / intracellular signal transduction / chromatin remodeling / positive regulation of protein phosphorylation / axon / phosphorylation / protein phosphorylation / focal adhesion / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / dendrite / apoptotic process / DNA damage response / positive regulation of cell population proliferation / protein-containing complex / nucleoplasm / ATP binding / identical protein binding / plasma membrane / 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 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-59U / Serine/threonine-protein kinase PAK 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.2 Å
AuthorsMaksimoska, J. / Marmorstein, R. / Wang, W.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pK a Polar Moiety.
Authors: Ndubaku, C.O. / Crawford, J.J. / Drobnick, J. / Aliagas, I. / Campbell, D. / Dong, P. / Dornan, L.M. / Duron, S. / Epler, J. / Gazzard, L. / Heise, C.E. / Hoeflich, K.P. / Jakubiak, D. / La, ...Authors: Ndubaku, C.O. / Crawford, J.J. / Drobnick, J. / Aliagas, I. / Campbell, D. / Dong, P. / Dornan, L.M. / Duron, S. / Epler, J. / Gazzard, L. / Heise, C.E. / Hoeflich, K.P. / Jakubiak, D. / La, H. / Lee, W. / Lin, B. / Lyssikatos, J.P. / Maksimoska, J. / Marmorstein, R. / Murray, L.J. / O'Brien, T. / Oh, A. / Ramaswamy, S. / Wang, W. / Zhao, X. / Zhong, Y. / Blackwood, E. / Rudolph, J.
History
DepositionAug 27, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 27, 2016Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Serine/threonine-protein kinase PAK 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9633
Polymers33,3671
Non-polymers5962
Water3,657203
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.965, 103.819, 123.542
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-727-

HOH

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Components

#1: Protein Serine/threonine-protein kinase PAK 1 / Alpha-PAK / p21-activated kinase 1 / PAK-1 / p65-PAK


Mass: 33367.242 Da / Num. of mol.: 1 / Fragment: Protein kinase domain residue 249-545 / Mutation: K299R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PAK1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q13153, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-59U / 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-8-ethyl-2-{[2-(1-methylpiperidin-4-yl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one


Mass: 518.053 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H32ClN7O
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 203 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.5 Å3/Da / Density % sol: 50.74 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 1 uL of PAK1 (9 mg/ml) with 1 uL of crystallization solution (0.1 M HEPES pH 7.0, 1 M NaCl, 25% PEG 3350, 10 mM DTT) at 4C

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Jun 12, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 17366 / % possible obs: 99.5 % / Redundancy: 4.8 % / Net I/σ(I): 10.1

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Processing

Software
NameVersionClassification
PHENIX1.8_1069refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementResolution: 2.2→30.82 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.84 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2464 865 5 %
Rwork0.1903 --
obs0.1931 17297 99.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.2→30.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2275 0 41 203 2519
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082361
X-RAY DIFFRACTIONf_angle_d1.1363202
X-RAY DIFFRACTIONf_dihedral_angle_d15.653897
X-RAY DIFFRACTIONf_chiral_restr0.071365
X-RAY DIFFRACTIONf_plane_restr0.004406
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1976-2.33520.32771410.24052664X-RAY DIFFRACTION98
2.3352-2.51540.28971430.22772701X-RAY DIFFRACTION99
2.5154-2.76840.2711440.22762734X-RAY DIFFRACTION100
2.7684-3.16870.27941440.22542726X-RAY DIFFRACTION100
3.1687-3.99080.22141460.15732762X-RAY DIFFRACTION100
3.9908-30.8230.20811470.16562845X-RAY DIFFRACTION98

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