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- PDB-5dey: Crystal structure of PAK1 in complex with an inhibitor compound G-5555 -

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Basic information

Entry
Database: PDB / ID: 5dey
TitleCrystal structure of PAK1 in complex with an inhibitor compound G-5555
ComponentsSerine/threonine-protein kinase PAK 1
KeywordsTRANSFERASE/TRANSFERASE 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 / 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 / RHOV GTPase cycle / branching morphogenesis of an epithelial tube / regulation of axonogenesis / Fc-gamma receptor signaling pathway involved in phagocytosis / RHOJ GTPase cycle / stimulatory C-type lectin receptor signaling pathway / RHOQ GTPase cycle / RHO GTPases activate PAKs / exocytosis / RHOU GTPase cycle / regulation of MAPK cascade / Sema3A PAK dependent Axon repulsion / CDC42 GTPase cycle / RHOH GTPase cycle / Generation of second messenger molecules / intercalated disc / ephrin receptor signaling pathway / Smooth Muscle Contraction / RAC2 GTPase cycle / RAC3 GTPase cycle / phosphorylation / RHO GTPases activate PKNs / positive regulation of JUN kinase activity / positive regulation of stress fiber assembly / ruffle / collagen binding / positive regulation of microtubule polymerization / EPHB-mediated forward signaling / RAC1 GTPase cycle / 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 / wound healing / MAPK6/MAPK4 signaling / Regulation of actin dynamics for phagocytic cup formation / G beta:gamma signalling through CDC42 / 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 / protein phosphorylation / axon / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / centrosome / DNA damage response / dendrite / positive regulation of cell population proliferation / apoptotic process / 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 ...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-59T / Serine/threonine-protein kinase PAK 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.1 Å
AuthorsOh, A. / Tam, C. / Wang, W.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pK a Polar Moiety.
Authors: Ndubaku, C.O. / Crawford, J.J. / Drobnick, J. / Aliagas, I. / Campbell, D. / Dong, P. / Dornan, L.M. / Duron, S. / Epler, J. / Gazzard, L. / Heise, C.E. / Hoeflich, K.P. / Jakubiak, D. / La, ...Authors: Ndubaku, C.O. / Crawford, J.J. / Drobnick, J. / Aliagas, I. / Campbell, D. / Dong, P. / Dornan, L.M. / Duron, S. / Epler, J. / Gazzard, L. / Heise, C.E. / Hoeflich, K.P. / Jakubiak, D. / La, H. / Lee, W. / Lin, B. / Lyssikatos, J.P. / Maksimoska, J. / Marmorstein, R. / Murray, L.J. / O'Brien, T. / Oh, A. / Ramaswamy, S. / Wang, W. / Zhao, X. / Zhong, Y. / Blackwood, E. / Rudolph, J.
History
DepositionAug 26, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 27, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 1, 2016Group: Data collection
Revision 1.2Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)67,5584
Polymers66,5732
Non-polymers9862
Water3,513195
1
A: Serine/threonine-protein kinase PAK 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7792
Polymers33,2861
Non-polymers4931
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Serine/threonine-protein kinase PAK 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7792
Polymers33,2861
Non-polymers4931
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)61.661, 81.863, 65.916
Angle α, β, γ (deg.)90.00, 106.40, 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: 33286.270 Da / Num. of mol.: 2 / Fragment: Protein kinase domain residue 249-545 / Mutation: D389N, T423E
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-59T / 8-[(trans-5-amino-1,3-dioxan-2-yl)methyl]-6-[2-chloro-4-(6-methylpyridin-2-yl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one


Mass: 492.957 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H25ClN6O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 195 / 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

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Sample preparation

CrystalDensity Matthews: 2.4 Å3/Da / Density % sol: 48.69 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop
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: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Oct 22, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 35169 / % possible obs: 93.4 % / Redundancy: 3.4 % / Net I/σ(I): 24.9

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementResolution: 2.1→34.585 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.83 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2275 1720 4.9 %
Rwork0.1834 --
obs0.1856 35132 92.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→34.585 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4497 0 70 195 4762
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0084650
X-RAY DIFFRACTIONf_angle_d1.0796293
X-RAY DIFFRACTIONf_dihedral_angle_d14.311751
X-RAY DIFFRACTIONf_chiral_restr0.043714
X-RAY DIFFRACTIONf_plane_restr0.005808
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.076-2.13710.355860.25241498X-RAY DIFFRACTION50
2.1371-2.20610.30251110.23432212X-RAY DIFFRACTION74
2.2061-2.28490.26921440.23632655X-RAY DIFFRACTION88
2.2849-2.37640.27911460.23522895X-RAY DIFFRACTION96
2.3764-2.48450.30811350.22152985X-RAY DIFFRACTION100
2.4845-2.61540.26721620.2122997X-RAY DIFFRACTION100
2.6154-2.77920.26781700.2192999X-RAY DIFFRACTION100
2.7792-2.99370.26071610.21773001X-RAY DIFFRACTION100
2.9937-3.29480.24071460.20353047X-RAY DIFFRACTION100
3.2948-3.7710.21391570.1842997X-RAY DIFFRACTION100
3.771-4.74910.19851500.14443052X-RAY DIFFRACTION100
4.7491-34.590.17611520.14893074X-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)
10.2941-0.01630.14570.1152-0.01090.1301-0.29770.11250.0311-0.3121-0.0516-0.10440.4716-0.1083-0.0020.60010.00650.19530.456-0.10770.517522.1533-21.5436.8762
21.1418-0.5249-0.66930.56550.69212.0525-0.0195-0.0331-0.1872-0.0828-0.0143-0.0017-0.33480.4503-0.06350.2344-0.064-0.03590.34590.00340.167123.92160.187421.0822
30.29960.09670.07150.16630.06330.419-0.07890.11370.16170.2732-0.08060.34780.38590.0118-0.01330.3612-0.03920.07020.2224-0.0260.4738-2.1927-15.6865-15.1171
40.7861.0131-0.5092-0.1676-0.81010.92670.0265-0.03950.13350.21860.03690.2806-0.06170.14790.00360.23180.05840.00590.1581-0.01850.252214.60245.2872-16.8802
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain A and resid 250:346
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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