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- PDB-9d51: Structure of PAK2 in complex with compound 12 -

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Basic information

Entry
Database: PDB / ID: 9d51
TitleStructure of PAK2 in complex with compound 12
ComponentsPAK-2p34
KeywordsTRANSFERASE / Serine/threonine-protein kinase / inhibitor
Function / homology
Function and homology information


Regulation of PAK-2p34 activity by PS-GAP/RHG10 / protein localization to cell-cell junction / Stimulation of the cell death response by PAK-2p34 / dendritic spine development / bicellular tight junction assembly / cardiac muscle hypertrophy / adherens junction assembly / Nef and signal transduction / Activation of RAC1 / positive regulation of extrinsic apoptotic signaling pathway ...Regulation of PAK-2p34 activity by PS-GAP/RHG10 / protein localization to cell-cell junction / Stimulation of the cell death response by PAK-2p34 / dendritic spine development / bicellular tight junction assembly / cardiac muscle hypertrophy / adherens junction assembly / Nef and signal transduction / Activation of RAC1 / positive regulation of extrinsic apoptotic signaling pathway / Ephrin signaling / CD28 dependent Vav1 pathway / negative regulation of stress fiber assembly / regulation of axonogenesis / RHOV GTPase cycle / RHOJ GTPase cycle / regulation of cytoskeleton organization / stimulatory C-type lectin receptor signaling pathway / RHOQ GTPase cycle / RHO GTPases activate PAKs / : / regulation of MAPK cascade / protein tyrosine kinase activator activity / RHOU GTPase cycle / CDC42 GTPase cycle / RHOH GTPase cycle / Generation of second messenger molecules / Sema3A PAK dependent Axon repulsion / RHOG GTPase cycle / Smooth Muscle Contraction / RAC2 GTPase cycle / RAC3 GTPase cycle / vascular endothelial growth factor receptor signaling pathway / cellular response to transforming growth factor beta stimulus / RAC1 GTPase cycle / CD209 (DC-SIGN) signaling / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / secretory granule / cellular response to starvation / Regulation of activated PAK-2p34 by proteasome mediated degradation / negative regulation of protein kinase activity / VEGFR2 mediated vascular permeability / FCERI mediated MAPK activation / MAPK6/MAPK4 signaling / small GTPase binding / VEGFA-VEGFR2 Pathway / cell-cell junction / cell migration / 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 / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / protein kinase activity / postsynaptic density / intracellular signal transduction / nuclear speck / protein phosphorylation / cadherin binding / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / apoptotic process / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / glutamatergic synapse / signal transduction / nucleoplasm / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
p21-activated kinase 2, catalytic domain / p21 activated kinase binding domain / : / CRIB domain superfamily / P21-Rho-binding domain / CRIB domain profile. / P21-Rho-binding domain / CRIB domain / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. ...p21-activated kinase 2, catalytic domain / p21 activated kinase binding domain / : / CRIB domain superfamily / P21-Rho-binding domain / CRIB domain profile. / P21-Rho-binding domain / CRIB domain / 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
Similarity search - Domain/homology
: / Serine/threonine-protein kinase PAK 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsCakici, O. / Suto, R.K. / Olland, A.M.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: To Be Published
Title: Identification of a p21-Activated Kinase 1 (PAK1) Inhibitor with 10-fold Selectivity Against PAK2
Authors: Johns, D. / Olejniczak, J. / Babbar, A. / Boone, C. / Cakici, O. / Cheng, M. / Cheng, Q. / Dementiev, A. / Eick, M. / Ferdyan, N. / Fontano, E. / Forman, A. / Goel, V. / Hirst, G. / ...Authors: Johns, D. / Olejniczak, J. / Babbar, A. / Boone, C. / Cakici, O. / Cheng, M. / Cheng, Q. / Dementiev, A. / Eick, M. / Ferdyan, N. / Fontano, E. / Forman, A. / Goel, V. / Hirst, G. / Kozlowski, R. / Lee, S. / Mehta, S. / Mowery, K. / Murray, B. / Nguyen, V. / Olland, A. / Phan, K. / Reich, S. / Rivera, L. / Sabat, M. / Sprengeler, P. / Srinivasan, K. / Sun, Z. / Suto, R. / Wilkinson, T. / Wang, C. / Yu, N. / Xu, M.
History
DepositionAug 13, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: PAK-2p34
A: PAK-2p34
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,2644
Polymers66,5192
Non-polymers7452
Water28816
1
B: PAK-2p34
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6322
Polymers33,2601
Non-polymers3721
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: PAK-2p34
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6322
Polymers33,2601
Non-polymers3721
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)61.629, 80.755, 66.742
Angle α, β, γ (deg.)90, 106.186, 90
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11B
21B

NCS domain segments:

Component-ID: 1 / Ens-ID: 1 / Beg auth comp-ID: GLU / Beg label comp-ID: GLU / End auth comp-ID: LYS / End label comp-ID: LYS / Auth asym-ID: B / Label asym-ID: A / Auth seq-ID: 231 - 521 / Label seq-ID: 4 - 294

Dom-ID
1
2

NCS ensembles : (Details: Local NCS retraints between domains: 1 2)

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Components

#1: Protein PAK-2p34 / p34 / C-t-PAK2


Mass: 33259.523 Da / Num. of mol.: 2 / Mutation: D368N, T402E, P498Q, M514A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PAK2 / Plasmid: pET-24a(+)
Details (production host): 6xHis-GST-TEV-PAK2_NEQA (228-524)
Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21-Star (DE3) / References: UniProt: Q13177
#2: Chemical ChemComp-A1A2Q / N~2~-{[(1s,4s)-4-aminocyclohexyl]methyl}-N~4~-[5-(trifluoromethyl)-1,3-thiazol-2-yl]pyrimidine-2,4-diamine


Mass: 372.412 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H19F3N6S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 16 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.41 Å3/Da / Density % sol: 48.95 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 20% (w/v) PEG 3350, 200 mM Ammonium tartrate dibasic

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.9201 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Nov 4, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 2.1→47.783 Å / Num. obs: 36183 / % possible obs: 98.6 % / Redundancy: 7.5 % / CC1/2: 0.996 / Rmerge(I) obs: 0.091 / Net I/σ(I): 7.4
Reflection shellResolution: 2.1→2.16 Å / Redundancy: 7.7 % / Rmerge(I) obs: 1.405 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 2947 / CC1/2: 0.657 / % possible all: 98.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→47.783 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.934 / SU B: 23.631 / SU ML: 0.257 / Cross valid method: FREE R-VALUE / ESU R: 0.243 / ESU R Free: 0.224
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2855 1790 4.95 %
Rwork0.2117 34375 -
all0.215 --
obs-36165 98.349 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 72.645 Å2
Baniso -1Baniso -2Baniso -3
1--0.441 Å2-0 Å2-0.511 Å2
2---0.567 Å2-0 Å2
3---1.117 Å2
Refinement stepCycle: LAST / Resolution: 2.1→47.783 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4510 0 50 16 4576
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0124637
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164546
X-RAY DIFFRACTIONr_angle_refined_deg2.5921.8636267
X-RAY DIFFRACTIONr_angle_other_deg0.8171.75610512
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.3875573
X-RAY DIFFRACTIONr_dihedral_angle_2_deg16.352520
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.42910869
X-RAY DIFFRACTIONr_dihedral_angle_6_deg15.7810191
X-RAY DIFFRACTIONr_chiral_restr0.1230.2723
X-RAY DIFFRACTIONr_chiral_restr_other0.0130.21
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.025253
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02937
X-RAY DIFFRACTIONr_nbd_refined0.2250.21081
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2170.24375
X-RAY DIFFRACTIONr_nbtor_refined0.190.22276
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0940.22674
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2090.2100
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0660.24
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1290.213
X-RAY DIFFRACTIONr_nbd_other0.2150.274
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.3380.28
X-RAY DIFFRACTIONr_mcbond_it7.4675.0482304
X-RAY DIFFRACTIONr_mcbond_other7.4645.0472304
X-RAY DIFFRACTIONr_mcangle_it9.2829.0252873
X-RAY DIFFRACTIONr_mcangle_other9.2819.0262874
X-RAY DIFFRACTIONr_scbond_it8.0085.482333
X-RAY DIFFRACTIONr_scbond_other7.9835.4812307
X-RAY DIFFRACTIONr_scangle_it10.3779.8733394
X-RAY DIFFRACTIONr_scangle_other10.399.8733357
X-RAY DIFFRACTIONr_lrange_it12.16848.9025152
X-RAY DIFFRACTIONr_lrange_other12.1948.8165122
X-RAY DIFFRACTIONr_ncsr_local_group_10.2240.057570
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)Weight position
11BX-RAY DIFFRACTIONLocal ncs0.22350.05005
12BX-RAY DIFFRACTIONLocal ncs0.22350.05005
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
2.1-2.1540.4321350.37125290.37427120.880.90698.23010.356
2.154-2.2130.3951130.34424610.34726250.9030.91598.05710.329
2.213-2.2770.3481550.32423720.32525680.910.92998.40340.301
2.277-2.3470.3161240.29322870.29524530.9340.94598.28780.278
2.347-2.4240.341350.27822590.28224390.9210.95698.1550.258
2.424-2.5090.3881140.28621720.29123230.930.95998.40720.264
2.509-2.6030.4051070.31621270.32122700.9270.95398.41410.29
2.603-2.7090.4061010.29219880.29821470.8960.95597.29860.271
2.709-2.8290.3021020.2519690.25321030.9460.9798.47840.221
2.829-2.9670.327830.22618780.2319890.9450.97498.59230.204
2.967-3.1270.376780.21918020.22419020.9110.97698.84330.205
3.127-3.3160.294720.21916870.22217840.940.97598.59870.214
3.316-3.5430.286710.21515980.21816950.9490.97698.46610.213
3.543-3.8250.277810.2114770.21415790.9550.97898.670.213
3.825-4.1880.264810.19413570.19814590.9530.97998.56070.206
4.188-4.6780.234700.16412150.16813140.9720.98597.7930.187
4.678-5.3930.267570.18510960.18911700.9580.98498.5470.216
5.393-6.5840.332420.2119410.2169950.9610.98198.7940.245
6.584-9.2240.189430.1477340.157830.9830.98899.23370.193
9.224-47.7830.26260.1744260.1794580.9730.97998.690.252
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)
10.55980.66410.19321.28540.21090.9010.044-0.09290.00520.0988-0.05340.12130.0309-0.06210.00930.06030.04840.06670.34850.00120.09988.8398-1.4518-16.5072
21.1113-0.4285-0.39031.96280.1992.0734-0.04430.0515-0.20670.02340.0205-0.03030.14310.07080.02390.02730.02880.01440.3561-0.00790.051722.6626-6.834516.3219
Refinement TLS groupSelection: ALL

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