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- PDB-4bie: Crystal Structures of Ask1-inhibitor Complexes -

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Basic information

Entry
Database: PDB / ID: 4bie
TitleCrystal Structures of Ask1-inhibitor Complexes
ComponentsMITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5
KeywordsTRANSFERASE / STRUCTURE BASED DESGIN
Function / homology
Function and homology information


cellular response to reactive nitrogen species / neuron intrinsic apoptotic signaling pathway in response to oxidative stress / IRE1-TRAF2-ASK1 complex / protein kinase complex / mitogen-activated protein kinase kinase kinase / programmed necrotic cell death / JUN kinase kinase kinase activity / endothelial cell apoptotic process / positive regulation of p38MAPK cascade / intrinsic apoptotic signaling pathway in response to oxidative stress ...cellular response to reactive nitrogen species / neuron intrinsic apoptotic signaling pathway in response to oxidative stress / IRE1-TRAF2-ASK1 complex / protein kinase complex / mitogen-activated protein kinase kinase kinase / programmed necrotic cell death / JUN kinase kinase kinase activity / endothelial cell apoptotic process / positive regulation of p38MAPK cascade / intrinsic apoptotic signaling pathway in response to oxidative stress / p38MAPK cascade / positive regulation of JUN kinase activity / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / MAP kinase kinase kinase activity / positive regulation of myoblast differentiation / positive regulation of cardiac muscle cell apoptotic process / stress-activated MAPK cascade / positive regulation of vascular associated smooth muscle cell proliferation / JNK cascade / cellular response to amino acid starvation / response to endoplasmic reticulum stress / response to ischemia / positive regulation of JNK cascade / apoptotic signaling pathway / cellular response to hydrogen peroxide / cellular response to tumor necrosis factor / cellular senescence / MAPK cascade / neuron apoptotic process / protein phosphatase binding / Oxidative Stress Induced Senescence / protein kinase activity / positive regulation of apoptotic process / protein domain specific binding / innate immune response / external side of plasma membrane / protein serine kinase activity / protein serine/threonine kinase activity / protein kinase binding / positive regulation of DNA-templated transcription / magnesium ion binding / protein homodimerization activity / protein-containing complex / ATP binding / identical protein binding / cytoplasm / cytosol
Similarity search - Function
MAP3K, TRAFs-binding domain / MAP3K, PH domain / MAP3K, deoxyribohydrolase domain / MAP3K, HisK-N-like globin domain / MAP3K TRAFs-binding domain / ASK kinase PH domain / HisK-N-like globin domain of the ASK signalosome / Deoxyribohydrolase (DRHyd) domain of the ASK signalosome / Sterile alpha motif/pointed domain superfamily / Phosphorylase Kinase; domain 1 ...MAP3K, TRAFs-binding domain / MAP3K, PH domain / MAP3K, deoxyribohydrolase domain / MAP3K, HisK-N-like globin domain / MAP3K TRAFs-binding domain / ASK kinase PH domain / HisK-N-like globin domain of the ASK signalosome / Deoxyribohydrolase (DRHyd) domain of the ASK signalosome / Sterile alpha motif/pointed domain superfamily / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-IE6 / Mitogen-activated protein kinase kinase kinase 5
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.36 Å
AuthorsSingh, O. / Shillings, A. / Craggs, P. / Wall, I. / Rowland, P. / Skarzynski, T. / Hobbs, C.I. / Hardwick, P. / Tanner, R. / Blunt, M. ...Singh, O. / Shillings, A. / Craggs, P. / Wall, I. / Rowland, P. / Skarzynski, T. / Hobbs, C.I. / Hardwick, P. / Tanner, R. / Blunt, M. / Witty, D.R. / Smith, K.J.
CitationJournal: Protein Sci. / Year: 2013
Title: Crystal Structures of Ask1-Inhibtor Complexes Provide a Platform for Structure Based Drug Design.
Authors: Singh, O. / Shillings, A. / Craggs, P. / Wall, I. / Rowland, P. / Skarzynski, T. / Hobbs, C.I. / Hardwick, P. / Tanner, R. / Blunt, M. / Witty, D.R. / Smith, K.J.
History
DepositionApr 10, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 3, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2013Group: Database references
Revision 1.2Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5
B: MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,9346
Polymers71,0772
Non-polymers8574
Water3,459192
1
A: MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9673
Polymers35,5381
Non-polymers4292
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9673
Polymers35,5381
Non-polymers4292
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)77.950, 77.950, 418.430
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522

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Components

#1: Protein MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 5 / ASK1 / APOPTOSIS SIGNAL-REGULATING KINASE 1 / ASK-1 / MAPK/ERK KINASE KINASE 5 / MEK KINASE 5 / MEKK 5


Mass: 35538.398 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, RESIDUES 660-977 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9
References: UniProt: Q99683, mitogen-activated protein kinase kinase kinase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-IE6 / N-(2-aminoethyl)-5-{2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl}thiophene-2-sulfonamide


Mass: 336.432 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H16N4O2S2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 192 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsEXPRESSED SEQUENCE CONTAINS THE MUTATION T838E

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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: 2.58 Å3/Da / Density % sol: 52.35 % / Description: NONE
Crystal growpH: 6.5
Details: 18% PEG3.4K, 0.2M NA ACETATE, 0.1M BIS-TRIS PH6.5, 0.2% ISOPROPANOL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.072
DetectorType: ADSC CCD / Detector: CCD / Date: Jul 15, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.072 Å / Relative weight: 1
ReflectionResolution: 2.36→68.04 Å / Num. obs: 30722 / % possible obs: 94.7 % / Observed criterion σ(I): 2 / Redundancy: 4.7 % / Biso Wilson estimate: 55.21 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 11.6
Reflection shellResolution: 2.36→2.49 Å / Redundancy: 4.2 % / Rmerge(I) obs: 0.45 / Mean I/σ(I) obs: 2.7 / % possible all: 94.6

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Processing

Software
NameVersionClassification
BUSTER2.11.1refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2CLQ

2clq


Resolution: 2.36→67.88 Å / Cor.coef. Fo:Fc: 0.9375 / Cor.coef. Fo:Fc free: 0.9195 / SU R Cruickshank DPI: 0.281 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.305 / SU Rfree Blow DPI: 0.232 / SU Rfree Cruickshank DPI: 0.226
Details: DEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2527 1547 5.04 %RANDOM
Rwork0.2103 ---
obs0.2124 30722 93.33 %-
Displacement parametersBiso mean: 50.63 Å2
Baniso -1Baniso -2Baniso -3
1-0.3609 Å20 Å20 Å2
2--0.3609 Å20 Å2
3----0.7218 Å2
Refine analyzeLuzzati coordinate error obs: 0.308 Å
Refinement stepCycle: LAST / Resolution: 2.36→67.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3981 0 56 192 4229
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014126HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.235573HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1418SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes104HARMONIC2
X-RAY DIFFRACTIONt_gen_planes596HARMONIC5
X-RAY DIFFRACTIONt_it4126HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.86
X-RAY DIFFRACTIONt_other_torsion19.6
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion524SEMIHARMONIC5
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_contact4973SEMIHARMONIC4
LS refinement shellResolution: 2.36→2.44 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.3166 158 5.39 %
Rwork0.2486 2771 -
all0.2522 2929 -
obs--93.33 %

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