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- PDB-5v19: Structure-based drug design of novel ASK1 inhibitors using a full... -

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Basic information

Entry
Database: PDB / ID: 5v19
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 / 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 / positive regulation of vascular associated smooth muscle cell proliferation / JNK cascade / response to endoplasmic reticulum stress / cellular response to amino acid starvation / apoptotic signaling pathway / response to ischemia / positive regulation of JNK cascade / cellular response to hydrogen peroxide / cellular senescence / MAPK cascade / 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 phosphorylation / protein domain specific binding / external side of plasma membrane / 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, 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 / Transferase(Phosphotransferase) 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 / 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
N-(1-ethyl-1H-pyrazol-4-yl)furan-3-carboxamide / Mitogen-activated protein kinase kinase kinase 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsDougan, D.R. / Lawson, J.D. / Lane, W.
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 1, 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)61,4304
Polymers61,0202
Non-polymers4102
Water1267
1
A: Mitogen-activated protein kinase kinase kinase 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,7152
Polymers30,5101
Non-polymers2051
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)30,7152
Polymers30,5101
Non-polymers2051
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.595, 78.595, 433.472
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-8V4 / N-(1-ethyl-1H-pyrazol-4-yl)furan-3-carboxamide


Mass: 205.213 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H11N3O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / 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: 3.17 Å3/Da / Density % sol: 61.16 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 6% polyethylene glycol 2000 MME ,0.05 M ammonium sulphate, 0.1M MES, pH 6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 6, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.1→50 Å / Num. obs: 15419 / % possible obs: 98.8 % / Redundancy: 6.8 % / Rmerge(I) obs: 0.086 / Rpim(I) all: 0.035 / Rrim(I) all: 0.093 / Χ2: 1.018 / Net I/σ(I): 11
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
3.1-3.157.40.7450.8790.2820.7990.898100
3.15-3.217.40.6280.9180.2390.6740.896100
3.21-3.277.20.5090.9330.1960.5470.939100
3.27-3.347.30.4410.9540.1690.4731.012100
3.34-3.417.10.3760.9570.1460.4051.049100
3.41-3.497.30.30.9660.1150.3231.083100
3.49-3.5870.2630.9730.1020.2841.114100
3.58-3.685.50.1930.9680.0840.2121.29583.9
3.68-3.785.80.2220.9780.0930.2421.2594.8
3.78-3.916.90.1470.9890.0580.1591.06899.7
3.91-4.046.80.1190.9940.0470.1291.034100
4.04-4.216.90.10.9960.0390.1071.008100
4.21-4.46.70.0840.9950.0330.0910.99699.6
4.4-4.636.80.0720.9970.0290.0781.00299.5
4.63-4.926.60.0690.9980.0270.0740.98499.9
4.92-5.36.80.0730.9970.0290.0790.992100
5.3-5.836.70.0770.9960.0310.0840.99499.9
5.83-6.676.60.0770.9930.0310.0830.99299.8
6.67-8.46.60.0540.9980.0230.0590.97199.6
8.4-505.90.0360.9990.0150.0390.95798.1

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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: 3.1→30 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.857 / SU B: 50.558 / SU ML: 0.383 / SU R Cruickshank DPI: 0.4324 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.48 / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2852 768 5 %RANDOM
Rwork0.2377 ---
obs0.24 14500 98.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 277.26 Å2 / Biso mean: 114.943 Å2 / Biso min: 56.91 Å2
Baniso -1Baniso -2Baniso -3
1-2.55 Å21.27 Å2-0 Å2
2--2.55 Å20 Å2
3----8.27 Å2
Refinement stepCycle: final / Resolution: 3.1→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4051 0 30 7 4088
Biso mean--117.6 88.19 -
Num. residues----510
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0194171
X-RAY DIFFRACTIONr_angle_refined_deg1.2681.985616
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6295503
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.42324.574188
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.45915747
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.8571518
X-RAY DIFFRACTIONr_chiral_restr0.0870.2600
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213134
LS refinement shellResolution: 3.099→3.179 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.379 60 -
Rwork0.283 1020 -
all-1080 -
obs--98.27 %
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)
10.0402-0.2561-0.18811.98270.62343.75740.0295-0.0284-0.0137-0.40670.05330.0652-0.48220.4063-0.08280.4-0.03540.0520.2216-0.12310.345324.87254.5743419.9148
20.0114-0.1096-0.05341.729-0.10371.27860.0371-0.0446-0.002-0.00370.02470.0802-0.18550.5715-0.06180.28-0.30770.06520.4775-0.15970.336335.018513.689429.4291
34.36113.33950.56055.36882.56391.70750.1480.84150.7244-0.28140.19520.0372-0.3406-0.1851-0.34320.5294-0.09370.06670.48420.09490.431536.257725.5369425.1227
41.9803-1.5417-1.47661.20921.18621.30610.20450.0478-0.309-0.287-0.10880.1909-0.61390.2399-0.09561.0113-0.62220.24150.4266-0.24740.32636.021328.927442.9475
52.6891-0.4591-0.70092.3861-0.36182.5865-0.1020.26940.22930.09390.2413-0.10680.4004-0.1844-0.13930.4293-0.1394-0.03260.1323-0.03790.375246.437467.3156454.5964
60.9747-0.0257-1.14531.1667-2.01264.99230.11570.3364-0.0730.06150.11050.103-0.3239-0.5868-0.22620.3175-0.1621-0.04170.36160.01110.34934.392467.3463449.6227
70.32240.6738-0.59961.874-0.33053.5114-0.09320.252-0.0115-0.03420.323-0.3220.4861-1.0201-0.22980.3254-0.3578-0.07460.51540.01340.396724.612149.879462.7143
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A671 - 704
2X-RAY DIFFRACTION2A705 - 820
3X-RAY DIFFRACTION3A821 - 842
4X-RAY DIFFRACTION4A843 - 939
5X-RAY DIFFRACTION5B670 - 704
6X-RAY DIFFRACTION6B705 - 755
7X-RAY DIFFRACTION7B756 - 940

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