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- PDB-4zjj: PAK1 in complex with (S)-N-(tert-butyl)-3-((2-chloro-5-ethyl-8-fl... -

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Basic information

Entry
Database: PDB / ID: 4zjj
TitlePAK1 in complex with (S)-N-(tert-butyl)-3-((2-chloro-5-ethyl-8-fluoro-dibenzodiazepin-11-yl)amino)pyrrolidine-1-carboxamide
ComponentsSerine/threonine-protein kinase PAK 1
KeywordsTRANSFERASE / PAK1 / inhibitor / kinase / allosteric
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 / 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 / ephrin receptor signaling pathway / RAC2 GTPase cycle / localization / 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 / 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 / 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 / protein serine kinase activity / focal adhesion / 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 / cytoplasm / cytosol
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-4OR / Serine/threonine-protein kinase PAK 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.2 Å
AuthorsGutmann, S. / Rummel, G.
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
DepositionApr 29, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jun 24, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2015Group: Database references
Revision 1.2May 8, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_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
C: Serine/threonine-protein kinase PAK 1
D: Serine/threonine-protein kinase PAK 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,53410
Polymers133,6544
Non-polymers1,8806
Water13,781765
1
A: Serine/threonine-protein kinase PAK 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8712
Polymers33,4131
Non-polymers4581
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)33,8712
Polymers33,4131
Non-polymers4581
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Serine/threonine-protein kinase PAK 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8963
Polymers33,4131
Non-polymers4822
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Serine/threonine-protein kinase PAK 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8963
Polymers33,4131
Non-polymers4822
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)110.330, 113.790, 116.360
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein
Serine/threonine-protein kinase PAK 1 / Alpha-PAK / p21-activated kinase 1 / PAK-1 / p65-PAK


Mass: 33413.414 Da / Num. of mol.: 4
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-4OR / (S)-N-(tert-butyl)-3-((2-chloro-5-ethyl-8-fluoro-dibenzodiazepin-11-yl)amino)pyrrolidine-1-carboxamide


Mass: 457.971 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H29ClFN5O
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 765 / 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: 2.73 Å3/Da / Density % sol: 54.99 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: Equal volumes (0.8 uL) of reservoir solution and protein solution were mixed. Reservoir solution: 16.8% (w/v) PEG3350, 0.2 M magnesium formate (dihydrate)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Dec 7, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→116.4 Å / Num. obs: 69148 / % possible obs: 99.9 % / Redundancy: 7.34 % / Biso Wilson estimate: 31.56 Å2 / Net I/σ(I): 13.8

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementResolution: 2.2→116.36 Å / Cor.coef. Fo:Fc: 0.925 / Cor.coef. Fo:Fc free: 0.9 / SU R Cruickshank DPI: 0.214 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.227 / SU Rfree Blow DPI: 0.186 / SU Rfree Cruickshank DPI: 0.182
RfactorNum. reflection% reflectionSelection details
Rfree0.2384 3742 5 %RANDOM
Rwork0.2013 ---
obs0.2032 74859 99.9 %-
Displacement parametersBiso mean: 33.86 Å2
Baniso -1Baniso -2Baniso -3
1-7.9108 Å20 Å20 Å2
2---10.0824 Å20 Å2
3---2.1716 Å2
Refine analyzeLuzzati coordinate error obs: 0.294 Å
Refinement stepCycle: 1 / Resolution: 2.2→116.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8177 0 130 765 9072
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018449HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0911496HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2835SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes193HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1309HARMONIC5
X-RAY DIFFRACTIONt_it8449HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.11
X-RAY DIFFRACTIONt_other_torsion16.43
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1167SEMIHARMONIC5
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_contact10584SEMIHARMONIC4
LS refinement shellResolution: 2.2→2.26 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3814 267 4.94 %
Rwork0.3404 5143 -
all0.3424 5410 -
obs--99.9 %
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)
11.24630.16860.36430.39460.16330.78060.0362-0.00380.0464-0.0115-0.0332-0.02260.02960.0095-0.0030.0215-0.0024-0.0006-0.04980.0025-0.05944.391340.117847.9735
21.7428-0.50170.69010.5253-0.35561.6471-0.02320.12210.0986-0.0054-0.0364-0.0073-0.0919-0.18210.05950.00630.0484-0.00480.04920.0169-0.1357-23.95440.949410.4252
31.6135-0.10410.34330.5202-0.13120.88510.05060.3785-0.0233-0.08030.02430.0842-0.0444-0.1141-0.0749-0.05230.0246-0.01060.0527-0.0052-0.0894-37.490415.930327.5271
42.0270.07010.38820.6345-0.06011.10550.08730.10530.01770.0419-0.0058-0.0678-0.01350.1419-0.0816-0.027-0.0022-0.0018-0.0651-0.0182-0.052316.727815.304330.4804
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }

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