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- PDB-5v24: Structure-based drug design of novel ASK1 inhibitors using a full... -

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Basic information

Entry
Database: PDB / ID: 5v24
TitleStructure-based drug design of novel ASK1 inhibitors using a fully integrated lead optimization strategy
ComponentsMitogen-activated protein kinase kinase kinase 5
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / TRANSFERASE / METAL-BINDING / APOPTOSIS / 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 / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / MAP kinase kinase kinase activity / 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 / neuron apoptotic process / Oxidative Stress Induced Senescence / 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 / cytosol / cytoplasm
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-8V7 / Mitogen-activated protein kinase kinase kinase 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsDougan, D.R. / Lawson, J.D.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Structure-based drug design of novel ASK1 inhibitors using an integrated lead optimization strategy.
Authors: Gibson, T.S. / Johnson, B. / Fanjul, A. / Halkowycz, P. / Dougan, D.R. / Cole, D. / Swann, S.
History
DepositionMar 2, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 29, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 12, 2017Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)61,6494
Polymers61,0202
Non-polymers6292
Water1,08160
1
A: Mitogen-activated protein kinase kinase kinase 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,8242
Polymers30,5101
Non-polymers3141
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)30,8242
Polymers30,5101
Non-polymers3141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.610, 78.610, 429.785
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522

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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: 30509.900 Da / Num. of mol.: 2 / Fragment: UNP residues 670-940
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP3K5, ASK1, MAPKKK5, MEKK5 / Plasmid: pEH8 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta 2(DE3) pLysS
References: UniProt: Q99683, mitogen-activated protein kinase kinase kinase
#2: Chemical ChemComp-8V7 / 2-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]-N-(pyridin-2-yl)-1,3-thiazole-4-carboxamide


Mass: 314.366 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H14N6OS
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 60 / 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: 3.14 Å3/Da / Density % sol: 60.84 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 6% polyethylene glycol 2000 MME, 0.1M MES, pH 6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.976 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 22, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 28407 / % possible obs: 98.9 % / Redundancy: 5.6 % / Rmerge(I) obs: 0.065 / Rpim(I) all: 0.03 / Rrim(I) all: 0.072 / Χ2: 1.001 / Net I/σ(I): 12.6 / Num. measured all: 159982
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.5-2.544.80.590.7850.2950.6630.98599.9
2.54-2.595.30.4790.8640.230.5331100
2.59-2.645.70.4050.9130.1850.4471.002100
2.64-2.6960.3370.9490.150.3691.012100
2.69-2.7560.3010.9520.1340.331.033100
2.75-2.8260.2320.970.1040.2540.978100
2.82-2.8960.20.9820.0890.221.00699.9
2.89-2.965.90.1640.9840.0740.1810.99499.9
2.96-3.0560.1360.990.060.1491.003100
3.05-3.1560.1140.9920.0510.1250.982100
3.15-3.265.90.0910.9950.040.11100
3.26-3.395.90.0760.9960.0340.0841.004100
3.39-3.555.90.0650.9970.0290.0720.966100
3.55-3.734.80.0710.9910.0360.081.06782.1
3.73-3.975.80.0530.9980.0240.0580.99999.9
3.97-4.275.70.050.9970.0220.0550.978100
4.27-4.75.70.0560.9970.0250.0611.00299.7
4.7-5.385.30.0570.9960.0270.0631.02100
5.38-6.785.30.0560.9960.0260.0621.05399.9
6.78-504.90.0350.9980.0170.0390.96697.1

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
REFMAC5.8.0135refinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→30 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.914 / SU B: 19.141 / SU ML: 0.21 / SU R Cruickshank DPI: 0.3853 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.385 / ESU R Free: 0.268
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2659 1430 5.1 %RANDOM
Rwork0.2343 ---
obs0.2359 26851 98.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 138.12 Å2 / Biso mean: 69.477 Å2 / Biso min: 36.98 Å2
Baniso -1Baniso -2Baniso -3
1-0.57 Å20.29 Å2-0 Å2
2--0.57 Å2-0 Å2
3----1.85 Å2
Refinement stepCycle: final / Resolution: 2.5→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4077 0 44 60 4181
Biso mean--46.67 54.43 -
Num. residues----512
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0194221
X-RAY DIFFRACTIONr_bond_other_d0.0020.024005
X-RAY DIFFRACTIONr_angle_refined_deg1.3091.9845689
X-RAY DIFFRACTIONr_angle_other_deg0.91539264
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9535507
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.58824.663193
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.03915752
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.1941518
X-RAY DIFFRACTIONr_chiral_restr0.0730.2604
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214702
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02924
LS refinement shellResolution: 2.501→2.566 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.365 95 -
Rwork0.301 1928 -
all-2023 -
obs--99.51 %
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)
18.9324-0.51312.40462.8750.03454.4145-0.0797-0.17240.4675-0.0431-0.16610.1178-0.0252-0.36250.24580.14280.04270.03760.10390.03070.105117.079965.789-14.8992
24.30850.2422-0.33611.34070.5832.69040.11610.2055-0.6365-0.4542-0.1838-0.11630.3395-0.30.06770.3363-0.0418-0.01850.24270.06380.14538.752656.234-15.0077
31.06610.2096-0.39112.1428-0.20822.94940.09710.0803-0.17520.0104-0.09540.17910.1954-0.5008-0.00180.1341-0.0947-0.0380.16670.05090.14363.802854.6411-0.7274
44.5013.69610.74933.88592.15423.6288-0.14960.4714-0.2477-0.0790.1081-0.06670.6514-0.54640.04150.4814-0.1215-0.11720.25740.00930.15872.103945.7055-6.1719
56.37434.24571.74484.01950.42233.15770.31890.5478-0.79280.2906-0.1161-0.08661.01510.188-0.20280.517-0.2082-0.0030.3933-0.11450.48414.579539.47484.48
60.7523-1.19150.33812.7806-0.7120.2060.18870.44470.0931-0.3837-0.4127-1.04010.23050.16640.2241.01870.0541-0.03670.7359-0.05840.996716.017134.78758.0351
74.37421.13462.26425.31450.22962.13970.22-0.2126-0.18480.7221-0.19170.36350.609-0.5833-0.02820.5122-0.27980.06960.3990.09360.243-1.308241.26614.1885
84.4743-1.03370.09494.0211-1.33622.715-0.01250.2561-0.0058-0.5268-0.00060.07310.05210.08540.01320.1702-0.0806-0.0150.06920.00180.0375-5.1322.406918.0643
91.5420.85590.61842.00680.85424.34230.02710.3142-0.093-0.19730.0892-0.2876-0.07260.6316-0.11640.0907-0.03310.04990.1816-0.01590.07049.40327.642325.2357
102.6234-0.3855-0.7414.09690.23335.497-0.08240.1691-0.028-0.12930.0669-0.208-0.70990.87450.01550.2657-0.28410.00240.3136-0.00630.128818.356123.455828.9575
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A671 - 684
2X-RAY DIFFRACTION2A685 - 731
3X-RAY DIFFRACTION3A732 - 817
4X-RAY DIFFRACTION4A818 - 842
5X-RAY DIFFRACTION5A843 - 876
6X-RAY DIFFRACTION6A877 - 897
7X-RAY DIFFRACTION7A898 - 939
8X-RAY DIFFRACTION8B670 - 718
9X-RAY DIFFRACTION9B719 - 842
10X-RAY DIFFRACTION10B843 - 940

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