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- PDB-4o0t: Back pocket flexibility provides group-II PAK selectivity for typ... -

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Basic information

Entry
Database: PDB / ID: 4o0t
TitleBack pocket flexibility provides group-II PAK selectivity for type 1 kinase inhibitors
ComponentsSerine/threonine-protein kinase PAK 1
Keywordstransferase/transferase inhibitor / PAK1 / 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-2OL / Serine/threonine-protein kinase PAK 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsOh, A. / 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 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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


Theoretical massNumber of molelcules
Total (without water)67,4953
Polymers67,0892
Non-polymers4061
Water41423
1
A: Serine/threonine-protein kinase PAK 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,9512
Polymers33,5451
Non-polymers4061
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Serine/threonine-protein kinase PAK 1


Theoretical massNumber of molelcules
Total (without water)33,5451
Polymers33,5451
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1750 Å2
ΔGint-7 kcal/mol
Surface area26760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.656, 79.170, 66.343
Angle α, β, γ (deg.)90.00, 106.97, 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: 33544.504 Da / Num. of mol.: 2 / Fragment: unp residues 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-2OL / 1-({1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-benzimidazol-6-yl}ethynyl)cyclohexanol


Mass: 406.481 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H26N6O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 23 / 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: 2.38 Å3/Da / Density % sol: 48.39 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 7
Details: crystals were grown at 19 C from 1.0 uL + 1.0 uL vapor diffusion drops containing 10 mg/mL protein, 1 mM ligand, 0.15 M DL-Malic Acid pH 7.0, 20% - 30% PEG 3350, 4% 1,3-Propanediol and 0.1 M ...Details: crystals were grown at 19 C from 1.0 uL + 1.0 uL vapor diffusion drops containing 10 mg/mL protein, 1 mM ligand, 0.15 M DL-Malic Acid pH 7.0, 20% - 30% PEG 3350, 4% 1,3-Propanediol and 0.1 M Sodium Malonate, VAPOR DIFFUSION, SITTING DROP, temperature 292K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1.00001 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 25, 2013
RadiationMonochromator: Liquid Nitrogen cooled Dual Crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 2.6→50 Å / Num. all: 19942 / Num. obs: 19822 / % possible obs: 99.4 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 2.6→2.69 Å / % possible all: 99

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Processing

Software
NameVersionClassification
B3data collection
PHASERphasing
PHENIX(phenix.refine: 1.8.2_1309)refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→49.513 Å / SU ML: 0.36 / σ(F): 1.34 / Phase error: 34.84 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2645 1003 5.07 %
Rwork0.2142 --
obs0.2168 19785 98.38 %
all-19942 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.6→49.513 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4436 0 30 23 4489
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0034542
X-RAY DIFFRACTIONf_angle_d0.7986146
X-RAY DIFFRACTIONf_dihedral_angle_d13.5381717
X-RAY DIFFRACTIONf_chiral_restr0.056707
X-RAY DIFFRACTIONf_plane_restr0.003785
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5744-2.71010.36791280.30622511X-RAY DIFFRACTION92
2.7101-2.87990.34491430.29032690X-RAY DIFFRACTION99
2.8799-3.10220.35011540.27722663X-RAY DIFFRACTION99
3.1022-3.41430.34711530.25792675X-RAY DIFFRACTION99
3.4143-3.90820.28371360.21382745X-RAY DIFFRACTION100
3.9082-4.92320.24061400.18282726X-RAY DIFFRACTION100
4.9232-49.52250.19391490.17872772X-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)
10.818-0.05510.02920.65670.85740.7919-0.39440.0573-0.62880.0940.04220.00540.185-0.1286-0.0430.31730.04550.04270.4295-0.05360.553622.119-21.70675.852
21.5768-0.8482-0.40311.78091.91743.20480.1617-0.2511-0.02050.1730.2622-0.0345-0.66970.53510.10780.49440.0095-0.0240.5183-0.01740.348623.4551-1.063621.0036
30.4752-0.85910.06220.67750.15431.1809-0.0045-0.02740.18240.4678-0.12640.27490.20080.1034-0.00610.5473-0.17150.05860.4712-0.05140.617-3.391-14.462-15.2505
41.16810.1604-0.4019-1.0528-0.56321.9397-0.23430.0124-0.0450.51160.08470.28590.2175-0.0214-0.00820.52050.03550.04480.3208-0.02540.488915.49335.3352-17.3653
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 251:346 )A251 - 346
2X-RAY DIFFRACTION2( CHAIN A AND RESID 347:541 )A347 - 541
3X-RAY DIFFRACTION3( CHAIN B AND RESID 255:346 )B255 - 346
4X-RAY DIFFRACTION4( CHAIN B AND RESID 347:541 )B347 - 541

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