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- PDB-4zy6: Crystal structure of P21-activated kinase 1 in complex with an in... -

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Basic information

Entry
Database: PDB / ID: 4zy6
TitleCrystal structure of P21-activated kinase 1 in complex with an inhibitor compound 29
ComponentsSerine/threonine-protein kinase PAK 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / PAK1 / Kinase / Inhibitor / Complex / 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-4T6 / Serine/threonine-protein kinase PAK 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsRouge, L. / Wang, W.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Structure-Guided Design of Group I Selective p21-Activated Kinase Inhibitors.
Authors: Crawford, J.J. / Lee, W. / Aliagas, I. / Mathieu, S. / Hoeflich, K.P. / Zhou, W. / Wang, W. / Rouge, L. / Murray, L. / La, H. / Liu, N. / Fan, P.W. / Cheong, J. / Heise, C.E. / Ramaswamy, S. ...Authors: Crawford, J.J. / Lee, W. / Aliagas, I. / Mathieu, S. / Hoeflich, K.P. / Zhou, W. / Wang, W. / Rouge, L. / Murray, L. / La, H. / Liu, N. / Fan, P.W. / Cheong, J. / Heise, C.E. / Ramaswamy, S. / Mintzer, R. / Liu, Y. / Chao, Q. / Rudolph, J.
History
DepositionMay 21, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 1, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 15, 2015Group: Database references
Revision 1.2Dec 16, 2015Group: Refinement description

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)68,0055
Polymers67,1472
Non-polymers8583
Water4,396244
1
A: Serine/threonine-protein kinase PAK 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0503
Polymers33,5741
Non-polymers4772
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase PAK 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9542
Polymers33,5741
Non-polymers3811
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)62.634, 82.241, 66.137
Angle α, β, γ (deg.)90.00, 106.11, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 33573.547 Da / Num. of mol.: 2 / Fragment: Protein kinase domain residue 249-545 / Mutation: D389N
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-4T6 / N~2~-[(7-chloro-1H-benzimidazol-6-yl)methyl]-N~4~-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine


Mass: 380.834 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H17ClN8
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 244 / 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: 2.44 Å3/Da / Density % sol: 49.53 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 25% PEG 3500, 0.2M Ammonium Sulfate and 0.1M Tris pH 8

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 2, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. obs: 9458 / % possible obs: 99.3 % / Redundancy: 3.7 % / Biso Wilson estimate: 42.85 Å2 / Net I/σ(I): 21.4

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.15→29.36 Å / Cor.coef. Fo:Fc: 0.9509 / Cor.coef. Fo:Fc free: 0.9178 / SU R Cruickshank DPI: 0.217 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.217 / SU Rfree Blow DPI: 0.187 / SU Rfree Cruickshank DPI: 0.188
RfactorNum. reflection% reflectionSelection details
Rfree0.2389 1754 5.03 %RANDOM
Rwork0.187 ---
obs0.1896 34882 99.25 %-
Displacement parametersBiso mean: 60.5 Å2
Baniso -1Baniso -2Baniso -3
1--3.7765 Å20 Å2-5.9233 Å2
2--0.942 Å20 Å2
3---2.8345 Å2
Refine analyzeLuzzati coordinate error obs: 0.304 Å
Refinement stepCycle: 1 / Resolution: 2.15→29.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4404 0 59 244 4707
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014543HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.156147HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1615SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes119HARMONIC2
X-RAY DIFFRACTIONt_gen_planes635HARMONIC5
X-RAY DIFFRACTIONt_it4543HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.07
X-RAY DIFFRACTIONt_other_torsion19.61
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion601SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5387SEMIHARMONIC4
LS refinement shellResolution: 2.15→2.22 Å / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.2235 132 4.6 %
Rwork0.2091 2740 -
all0.2097 2872 -
obs--99.25 %
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)
13.12120.3322-0.72674.56820.90072.9804-0.54020.6484-1.0768-0.570.4724-0.13250.46180.01220.06780.4411-0.0850.15970.4715-0.34830.550921.9639-22.43198.156
22.64740.2790.20722.1361.18493.9426-0.17650.2332-0.1111-0.05980.2676-0.1988-0.450.6922-0.09120.283-0.02720.03370.2803-0.03410.120324.4332-0.433621.3443
31.701-0.01760.30325.74960.56572.1005-0.0918-0.183-0.11590.9003-0.17890.54650.4096-0.31810.27080.4944-0.0790.22620.194-0.03360.3408-2.3394-15.9257-15.185
41.96190.3977-1.07620.9186-0.41242.83350.0667-0.32350.18120.1539-0.04730.1052-0.16510.2331-0.01940.29620.00180.06580.1801-0.02440.202915.21814.835-16.8792
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|251 - A|346 }
2X-RAY DIFFRACTION2{ A|347 - A|541 A|601 }
3X-RAY DIFFRACTION3{ B|255 - B|346 }
4X-RAY DIFFRACTION4{ B|347 - B|541 B|601 }

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