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- PDB-4zy5: Crystal Structure of p21-activated kinase 1 in complex with an in... -

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Basic information

Entry
Database: PDB / ID: 4zy5
TitleCrystal Structure of p21-activated kinase 1 in complex with an inhibitor compound 17
ComponentsSerine/threonine-protein kinase PAK 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / 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-4T5 / Serine/threonine-protein kinase PAK 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 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

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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)68,0727
Polymers67,1472
Non-polymers9255
Water1,13563
1
A: Serine/threonine-protein kinase PAK 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0934
Polymers33,5741
Non-polymers5203
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)33,9793
Polymers33,5741
Non-polymers4062
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)62.566, 81.900, 65.800
Angle α, β, γ (deg.)90.00, 106.04, 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
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-4T5 / N~2~-[(trans-4-aminocyclohexyl)methyl]-N~4~-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine


Mass: 327.427 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H25N7
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: 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
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 63 / 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: 2.41 Å3/Da / Density % sol: 49.02 %
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: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 29, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.35→50 Å / Num. obs: 7237 / % possible obs: 97.7 % / Redundancy: 3.6 % / Net I/σ(I): 16.7

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.35→48.47 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.26 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2295 1318 5.06 %
Rwork0.1948 --
obs0.1966 26032 97.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.35→48.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4439 0 62 63 4564
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044590
X-RAY DIFFRACTIONf_angle_d0.8526205
X-RAY DIFFRACTIONf_dihedral_angle_d13.2621730
X-RAY DIFFRACTIONf_chiral_restr0.03714
X-RAY DIFFRACTIONf_plane_restr0.004785
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3495-2.44360.29261250.25812411X-RAY DIFFRACTION87
2.4436-2.55480.29331300.25792662X-RAY DIFFRACTION95
2.5548-2.68950.28391420.23322775X-RAY DIFFRACTION99
2.6895-2.8580.27851470.22472798X-RAY DIFFRACTION99
2.858-3.07860.26221510.22012764X-RAY DIFFRACTION100
3.0786-3.38830.23051370.212836X-RAY DIFFRACTION100
3.3883-3.87850.22491690.18482800X-RAY DIFFRACTION100
3.8785-4.88570.19051490.16822814X-RAY DIFFRACTION100
4.8857-48.48060.21621680.17612854X-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)
10.86010.181-0.49640.8351-0.24471.8852-0.90150.0328-1.7277-0.1592-0.4437-0.16450.47730.0153-1.34910.56570.10880.22730.4577-0.48460.852221.952-20.74587.0947
21.8417-0.4803-0.28441.1550.68491.8848-0.1579-0.0586-0.04650.02150.1722-0.1065-0.21890.340300.34330.0125-0.02850.4491-0.02120.335224.72220.525521.1982
30.3972-0.03430.34930.24610.15950.4639-0.25850.0795-0.09480.3779-0.11010.1490.5267-0.2183-0.00080.6078-0.05190.12340.3787-0.0410.5524-2.3825-14.8826-15.1616
40.90620.2928-0.11360.0468-0.43361.2024-0.0161-0.18870.09670.06380.00060.1233-0.03250.053800.36120.01720.00230.3239-0.02660.327114.93885.7245-16.1482
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain A and resid 251:346
2X-RAY DIFFRACTION2chain A and resid 347:541 or chain A and resid 601
3X-RAY DIFFRACTION3chain B and resid 255:346
4X-RAY DIFFRACTION4chain B and resid 347:541 or chain B and resid 601

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