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- PDB-5vil: Crystal structure of ASK1 kinase domain with a potent inhibitor (... -

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Basic information

Entry
Database: PDB / ID: 5vil
TitleCrystal structure of ASK1 kinase domain with a potent inhibitor (analog 6)
ComponentsMitogen-activated protein kinase kinase kinase 5
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase drug discovery / TRANSFERASE-TRANSFERASE INHIBITOR complex
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 / positive regulation of cardiac muscle cell apoptotic process / p38MAPK cascade / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / MAP kinase kinase kinase activity / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / positive regulation of protein kinase activity / positive regulation of myoblast differentiation / stress-activated MAPK cascade / positive regulation of JUN kinase activity / JNK cascade / positive regulation of vascular associated smooth muscle cell proliferation / cellular response to amino acid starvation / response to endoplasmic reticulum stress / response to ischemia / apoptotic signaling pathway / positive regulation of JNK cascade / cellular response to hydrogen peroxide / MAPK cascade / cellular senescence / cellular response to tumor necrosis factor / protein phosphatase binding / Oxidative Stress Induced Senescence / neuron apoptotic process / protein kinase activity / positive regulation of apoptotic process / protein domain specific binding / external side of plasma membrane / protein phosphorylation / innate immune response / 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, deoxyribohydrolase domain / MAP3K, HisK-N-like globin domain / HisK-N-like globin domain of the ASK signalosome / Deoxyribohydrolase (DRHyd) domain of the ASK signalosome / MAP3K, TRAFs-binding domain / MAP3K, PH domain / MAP3K TRAFs-binding domain / ASK kinase PH domain / Sterile alpha motif/pointed domain superfamily / Transferase(Phosphotransferase) domain 1 ...MAP3K, deoxyribohydrolase domain / MAP3K, HisK-N-like globin domain / HisK-N-like globin domain of the ASK signalosome / Deoxyribohydrolase (DRHyd) domain of the ASK signalosome / MAP3K, TRAFs-binding domain / MAP3K, PH domain / MAP3K TRAFs-binding domain / ASK kinase PH domain / Sterile alpha motif/pointed domain superfamily / 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-9E1 / Mitogen-activated protein kinase kinase kinase 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.64 Å
AuthorsJasti, J. / Chang, J. / Kurumbail, R.
CitationJournal: Eur J Med Chem / Year: 2017
Title: Rational approach to highly potent and selective apoptosis signal-regulating kinase 1 (ASK1) inhibitors.
Authors: Lovering, F. / Morgan, P. / Allais, C. / Aulabaugh, A. / Brodfuehrer, J. / Chang, J. / Coe, J. / Ding, W. / Dowty, H. / Fleming, M. / Frisbie, R. / Guzova, J. / Hepworth, D. / Jasti, J. / ...Authors: Lovering, F. / Morgan, P. / Allais, C. / Aulabaugh, A. / Brodfuehrer, J. / Chang, J. / Coe, J. / Ding, W. / Dowty, H. / Fleming, M. / Frisbie, R. / Guzova, J. / Hepworth, D. / Jasti, J. / Kortum, S. / Kurumbail, R. / Mohan, S. / Papaioannou, N. / Strohbach, J.W. / Vincent, F. / Lee, K. / Zapf, C.W.
History
DepositionApr 17, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 17, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.2Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mitogen-activated protein kinase kinase kinase 5
B: Mitogen-activated protein kinase kinase kinase 5
C: Mitogen-activated protein kinase kinase kinase 5
D: Mitogen-activated protein kinase kinase kinase 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,89712
Polymers131,9184
Non-polymers1,9788
Water2,486138
1
A: Mitogen-activated protein kinase kinase kinase 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4743
Polymers32,9801
Non-polymers4952
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)33,6305
Polymers32,9801
Non-polymers6514
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Mitogen-activated protein kinase kinase kinase 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3962
Polymers32,9801
Non-polymers4161
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Mitogen-activated protein kinase kinase kinase 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3962
Polymers32,9801
Non-polymers4161
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)40.540, 132.090, 135.220
Angle α, β, γ (deg.)90.00, 92.82, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Mitogen-activated protein kinase kinase kinase 5 / Apoptosis signal-regulating kinase 1 / ASK-1 / MAPK/ERK kinase kinase 5 / MEKK 5


Mass: 32979.617 Da / Num. of mol.: 4 / Fragment: UNP residues 659-951
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP3K5, ASK1, MAPKKK5, MEKK5 / Production host: Escherichia coli (E. coli)
References: UniProt: Q99683, mitogen-activated protein kinase kinase kinase
#2: Chemical
ChemComp-9E1 / 2-methoxy-N-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}-5-sulfamoylbenzamide


Mass: 416.454 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H20N6O4S
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 138 / Source method: isolated from a natural source / Formula: H2O

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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: 2.74 Å3/Da / Density % sol: 55.13 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 20% PEG 3350, 0.2M ammonium chloride, 0.1M Bis-Tris (pH 6.1-6.6), and 10% glycerol.
PH range: 6.1-6.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 23, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.64→135 Å / Num. obs: 34591 / % possible obs: 82.5 % / Redundancy: 3.1 % / Biso Wilson estimate: 76.18 Å2 / Rsym value: 0.031 / Net I/σ(I): 23.9
Reflection shellResolution: 2.64→3.73 Å / Redundancy: 2.9 % / Mean I/σ(I) obs: 9 / Num. unique obs: 19830 / Rsym value: 0.109 / % possible all: 73.5

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4BF2

4bf2


Resolution: 2.64→135 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.926 / Rfactor Rfree error: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 2.327 / SU Rfree Blow DPI: 0.292
RfactorNum. reflection% reflectionSelection details
Rfree0.213 1773 5.13 %RANDOM
Rwork0.18 ---
obs0.182 34567 82.7 %-
Displacement parametersBiso mean: 122.72 Å2
Baniso -1Baniso -2Baniso -3
1--11.1184 Å20 Å2-0.2685 Å2
2--17.3541 Å20 Å2
3----6.2357 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: 1 / Resolution: 2.64→135 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8584 0 132 138 8854
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.019020HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1712252HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3144SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes224HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1396HARMONIC5
X-RAY DIFFRACTIONt_it9020HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.77
X-RAY DIFFRACTIONt_other_torsion20.64
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1120SEMIHARMONIC5
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_contact10562SEMIHARMONIC4
LS refinement shellResolution: 2.64→2.72 Å / Rfactor Rfree error: 0 / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.286 -5.05 %
Rwork0.215 714 -
all0.218 752 -
obs--20.68 %
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)
11.74750.87070.71577.72561.64584.27240.06320.1803-0.4310.12850.0808-0.67010.62870.1743-0.144-0.25620.08260.1103-0.37430.0274-0.00283.763315.964466.2127
21.82310.10720.88024.35060.92213.2332-0.0407-0.18950.18670.8006-0.0106-0.4373-0.04540.41310.0514-0.12820.011-0.0041-0.21240.0398-0.04648.185449.559484.7247
34.3683-1.42042.150111.413-7.261610.6521-0.4852-0.5209-1.2953-0.09551.14981.23040.8344-0.8958-0.6646-0.5872-0.06150.194-0.42310.603-0.206217.309620.350216.6425
44.4422-2.15133.69087.1078-4.29079.1542-1.2244-0.31250.71850.72550.53340.0268-2.6759-0.93410.69110.4898-0.0728-0.4717-0.46460.2316-0.617916.567254.4507-1.505
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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