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- PDB-4p90: Crystal structure of the kinase domain of human PAK1 in complex w... -

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Basic information

Entry
Database: PDB / ID: 4p90
TitleCrystal structure of the kinase domain of human PAK1 in complex with compound 15
ComponentsSerine/threonine-protein kinase PAK 1
KeywordsTransferase/Transferase inhibitor / Inhibitor / kinase / 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 / Ephrin signaling / CD28 dependent Vav1 pathway / 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 / Ephrin signaling / CD28 dependent Vav1 pathway / positive regulation of intracellular estrogen receptor signaling pathway / regulation of axonogenesis / branching morphogenesis of an epithelial tube / RHOV GTPase cycle / phosphorylation / RHOJ GTPase cycle / stimulatory C-type lectin receptor signaling pathway / RHOQ GTPase cycle / exocytosis / RHO GTPases activate PAKs / Fc-gamma receptor signaling pathway involved in phagocytosis / regulation of MAPK cascade / RHOU GTPase cycle / CDC42 GTPase cycle / Generation of second messenger molecules / RHOH GTPase cycle / ephrin receptor signaling pathway / Sema3A PAK dependent Axon repulsion / intercalated disc / Smooth Muscle Contraction / RAC2 GTPase cycle / RAC3 GTPase cycle / RHO GTPases activate PKNs / positive regulation of JUN kinase activity / positive regulation of stress fiber assembly / collagen binding / ruffle / positive regulation of microtubule polymerization / EPHB-mediated forward signaling / RAC1 GTPase cycle / CD209 (DC-SIGN) signaling / neuron projection morphogenesis / cellular response to starvation / Signal transduction by L1 / VEGFR2 mediated vascular permeability / actin filament / regulation of actin cytoskeleton organization / FCERI mediated MAPK activation / wound healing / MAPK6/MAPK4 signaling / positive regulation of peptidyl-serine phosphorylation / Regulation of actin dynamics for phagocytic cup formation / Z disc / ruffle membrane / G beta:gamma signalling through CDC42 / cell migration / cell-cell junction / lamellipodium / chromosome / actin cytoskeleton organization / nuclear membrane / protein autophosphorylation / eukaryotic translation initiation factor 2alpha kinase activity / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / positive regulation of protein phosphorylation / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / positive regulation of cell migration / protein phosphorylation / chromatin remodeling / axon / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / centrosome / apoptotic process / positive regulation of cell population proliferation / dendrite / DNA damage response / protein-containing complex / nucleoplasm / ATP binding
Similarity search - Function
p21 activated kinase binding domain / : / CRIB domain superfamily / P21-Rho-binding domain / CRIB domain profile. / P21-Rho-binding domain / CRIB domain / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...p21 activated kinase binding domain / : / CRIB domain superfamily / P21-Rho-binding domain / CRIB domain profile. / P21-Rho-binding domain / CRIB domain / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-2K0 / Serine/threonine-protein kinase PAK 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.49 Å
AuthorsFerguson, A.D.
CitationJournal: MEDCHEMCOMM / Year: 2014
Title: Identification and optimisation of 7-azaindole PAK1 inhibitors with improved potency and kinase selectivity.
Authors: McCoull, W. / Hennessy, E.J. / Blades, K. / Box, M.R. / Chuaqui, C. / Dowling, J.E. / Davies, C.D. / Ferguson, A.D. / Goldberg, F.W. / Howe, N.J. / Kemmitt, P.D. / Lamont, G.M. / Madden, K. ...Authors: McCoull, W. / Hennessy, E.J. / Blades, K. / Box, M.R. / Chuaqui, C. / Dowling, J.E. / Davies, C.D. / Ferguson, A.D. / Goldberg, F.W. / Howe, N.J. / Kemmitt, P.D. / Lamont, G.M. / Madden, K. / McWhirter, C. / Varnes, J.G. / Ward, R.A. / Williams, J.D. / Yang, B.
History
DepositionApr 1, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 10, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 24, 2014Group: Other
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_source / entity_src_gen / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_assembly / pdbx_struct_oper_list / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_source.pdbx_synchrotron_site / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation / _refine_hist.number_atoms_solvent / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_ligand / _refine_hist.pdbx_number_atoms_nucleic_acid
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)67,4164
Polymers66,5442
Non-polymers8722
Water77543
1
A: Serine/threonine-protein kinase PAK 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7082
Polymers33,2721
Non-polymers4361
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)33,7082
Polymers33,2721
Non-polymers4361
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)62.400, 83.360, 66.020
Angle α, β, γ (deg.)90.00, 105.04, 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: 33272.242 Da / Num. of mol.: 2 / Mutation: D389N, T423E, E503D
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-2K0 / [2-chloro-5-(hydroxymethyl)phenyl]{5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}methanone


Mass: 435.906 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H22ClN5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 43 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.49 Å3/Da / Density % sol: 50.64 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.6
Details: 0.2M ammonium sulphate, 16% PEG 3350, 0.1M Hepes (pH 7.6)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Sep 19, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 2.49→83.36 Å / Num. all: 64319 / Num. obs: 22335 / % possible obs: 97.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.9 % / Biso Wilson estimate: 71.55 Å2 / Rmerge(I) obs: 0.041 / Net I/σ(I): 14.4
Reflection shellResolution: 2.49→2.63 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.569 / Mean I/σ(I) obs: 1.4 / % possible all: 96.7

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Processing

SoftwareName: BUSTER / Version: 2.11.5 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1YHV

1yhv


Resolution: 2.49→50.64 Å / Cor.coef. Fo:Fc: 0.9357 / Cor.coef. Fo:Fc free: 0.9282 / SU R Cruickshank DPI: 0.477 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.439 / SU Rfree Blow DPI: 0.24 / SU Rfree Cruickshank DPI: 0.248
RfactorNum. reflection% reflectionSelection details
Rfree0.2253 1147 5.14 %RANDOM
Rwork0.2085 ---
obs0.2094 22308 96.99 %-
Displacement parametersBiso mean: 87.18 Å2
Baniso -1Baniso -2Baniso -3
1--7.7659 Å20 Å2-13.929 Å2
2--2.1586 Å20 Å2
3---5.6073 Å2
Refine analyzeLuzzati coordinate error obs: 0.462 Å
Refinement stepCycle: 1 / Resolution: 2.49→50.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4187 0 62 43 4292
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014321HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.155838HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1550SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes115HARMONIC2
X-RAY DIFFRACTIONt_gen_planes595HARMONIC5
X-RAY DIFFRACTIONt_it4321HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.93
X-RAY DIFFRACTIONt_other_torsion19.66
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion568SEMIHARMONIC5
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_contact4882SEMIHARMONIC4
LS refinement shellResolution: 2.49→2.61 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2795 159 5.59 %
Rwork0.2478 2686 -
all0.2495 2845 -
obs--96.99 %
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)
13.40490.4125-3.04915.6285-3.21018.0361-0.1808-0.1419-0.58330.52790.28250.6764-0.4782-0.601-0.1017-0.2225-0.00980.0876-0.20680.0782-0.222-1.0859-23.229715.1449
20.99721-0.19562.23040.17451.7767-0.0051-0.24260.11060.5764-0.03790.53690.15010.02310.04290.0330.05150.1824-0.1764-0.0157-0.113731.841123.196814.7822
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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