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- PDB-4zlo: Serine/threonine-protein kinase PAK1 complexed with a dibenzodiaz... -

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Basic information

Entry
Database: PDB / ID: 4zlo
TitleSerine/threonine-protein kinase PAK1 complexed with a dibenzodiazepine: identification of an allosteric site on PAK1
ComponentsSerine/threonine-protein kinase PAK 1
KeywordsTransferase/transferase inhibitor / dibenzodazepine / PAK1 / kinase / allosteric inhibitor / 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 / positive regulation of intracellular estrogen receptor signaling pathway / Ephrin signaling ...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 / positive regulation of intracellular estrogen receptor signaling pathway / Ephrin signaling / RHOV GTPase cycle / DSCAM interactions / regulation of axonogenesis / branching morphogenesis of an epithelial tube / Fc-gamma receptor signaling pathway involved in phagocytosis / RHOJ GTPase cycle / exocytosis / RHOQ GTPase cycle / RHO GTPases activate PAKs / stimulatory C-type lectin receptor signaling pathway / regulation of MAPK cascade / CDC42 GTPase cycle / RHOH GTPase cycle / RHOU GTPase cycle / Sema3A PAK dependent Axon repulsion / Generation of second messenger molecules / intercalated disc / Smooth Muscle Contraction / localization / ephrin receptor signaling pathway / RAC2 GTPase cycle / RAC3 GTPase cycle / positive regulation of JUN kinase activity / RHO GTPases activate PKNs / positive regulation of microtubule polymerization / positive regulation of stress fiber assembly / ruffle / collagen binding / RAC1 GTPase cycle / EPHB-mediated forward signaling / 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 / intracellular signal transduction / positive regulation of cell migration / chromatin remodeling / positive regulation of protein phosphorylation / phosphorylation / axon / protein phosphorylation / focal adhesion / protein serine kinase activity / protein serine/threonine kinase activity / centrosome / apoptotic process / DNA damage response / dendrite / 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-4PV / Serine/threonine-protein kinase PAK 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.5 Å
AuthorsBellamacina, C.R. / Bussiere, D.E.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor.
Authors: Karpov, A.S. / Amiri, P. / Bellamacina, C. / Bellance, M.H. / Breitenstein, W. / Daniel, D. / Denay, R. / Fabbro, D. / Fernandez, C. / Galuba, I. / Guerro-Lagasse, S. / Gutmann, S. / Hinh, L. ...Authors: Karpov, A.S. / Amiri, P. / Bellamacina, C. / Bellance, M.H. / Breitenstein, W. / Daniel, D. / Denay, R. / Fabbro, D. / Fernandez, C. / Galuba, I. / Guerro-Lagasse, S. / Gutmann, S. / Hinh, L. / Jahnke, W. / Klopp, J. / Lai, A. / Lindvall, M.K. / Ma, S. / Mobitz, H. / Pecchi, S. / Rummel, G. / Shoemaker, K. / Trappe, J. / Voliva, C. / Cowan-Jacob, S.W. / Marzinzik, A.L.
History
DepositionMay 1, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 5, 2015Provider: repository / Type: Initial release

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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)67,0994
Polymers66,6782
Non-polymers4202
Water2,180121
1
A: Serine/threonine-protein kinase PAK 1
hetero molecules

B: Serine/threonine-protein kinase PAK 1


Theoretical massNumber of molelcules
Total (without water)67,0994
Polymers66,6782
Non-polymers4202
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_554x,y,z-11
Buried area1520 Å2
ΔGint-9 kcal/mol
Surface area25640 Å2
MethodPISA
2


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area950 Å2
ΔGint-11 kcal/mol
Surface area26210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.514, 79.340, 65.789
Angle α, β, γ (deg.)90.00, 108.11, 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: 33339.227 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Residue 177 is phosphorylated Threonine / 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-4PV / 2,8-difluoro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine


Mass: 328.359 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18F2N4
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / 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: 2.36 Å3/Da / Density % sol: 47.94 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 22-27% PEG3350, 500-700MM NACL, 100MM BIS-TRIS, PH 6.5

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cryo conditions
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54178 Å
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Jan 7, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.5→62.5 Å / Num. all: 21368 / Num. obs: 21368 / % possible obs: 98.8 % / Redundancy: 3.2 % / Biso Wilson estimate: 64.1 Å2 / Net I/σ(I): 13.3
Reflection shellResolution: 2.5→2.77 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.415 / Mean I/σ(I) obs: 2.6 / % possible all: 96

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementResolution: 2.5→52.31 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.9161 / SU R Cruickshank DPI: 0.477 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.459 / SU Rfree Blow DPI: 0.243 / SU Rfree Cruickshank DPI: 0.248
RfactorNum. reflection% reflectionSelection details
Rfree0.2224 1081 5.06 %RANDOM
Rwork0.1946 ---
obs0.196 21368 98.8 %-
Displacement parametersBiso mean: 62.7 Å2
Baniso -1Baniso -2Baniso -3
1--2.5514 Å20 Å2-7.5359 Å2
2---1.9211 Å20 Å2
3---4.4725 Å2
Refine analyzeLuzzati coordinate error obs: 0.315 Å
Refinement stepCycle: 1 / Resolution: 2.5→52.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4066 0 30 121 4217
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014182HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.135674HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1429SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes94HARMONIC2
X-RAY DIFFRACTIONt_gen_planes616HARMONIC5
X-RAY DIFFRACTIONt_it4182HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.82
X-RAY DIFFRACTIONt_other_torsion18.01
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion581SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies1HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4808SEMIHARMONIC4
LS refinement shellResolution: 2.5→2.62 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.28 123 4.61 %
Rwork0.2094 2545 -
all0.2125 2668 -
obs--98.8 %
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)
11.3221-0.6516-0.61352.0107-0.44072.08640.01820.22340.0221-0.1094-0.0894-0.15820.1047-0.07060.0712-0.1117-0.0430.011-0.11620.0036-0.113932.11595.1771-14.5141
23.3059-0.3145-1.2152.6534-0.52033.0827-0.17950.1178-0.32180.02550.00120.2681-0.0143-0.41360.1783-0.1796-0.06610.0196-0.1233-0.0205-0.2129-1.83210.976113.3558
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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