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- PDB-5uox: Structure-Based Design of ASK1 Inhibitors as Potential First-in-C... -

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Basic information

Entry
Database: PDB / ID: 5uox
TitleStructure-Based Design of ASK1 Inhibitors as Potential First-in-Class Agents for Heart Failure
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 / protein serine kinase activity / innate immune response / 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-8GY / Mitogen-activated protein kinase kinase kinase 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.5 Å
AuthorsDougan, D.R.
CitationJournal: ACS Med Chem Lett / Year: 2017
Title: Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure.
Authors: Lanier, M. / Pickens, J. / Bigi, S.V. / Bradshaw-Pierce, E.L. / Chambers, A. / Cheruvallath, Z.S. / Cole, D. / Dougan, D.R. / Ermolieff, J. / Gibson, T. / Halkowycz, P. / Hirokawa, A. / ...Authors: Lanier, M. / Pickens, J. / Bigi, S.V. / Bradshaw-Pierce, E.L. / Chambers, A. / Cheruvallath, Z.S. / Cole, D. / Dougan, D.R. / Ermolieff, J. / Gibson, T. / Halkowycz, P. / Hirokawa, A. / Ivetac, A. / Miura, J. / Nunez, E. / Sabat, M. / Tyhonas, J. / Wang, H. / Wang, X. / Swann, S.
History
DepositionFeb 1, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 7, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Data collection / Refinement description / Category: diffrn_detector / software / Item: _diffrn_detector.detector / _software.name
Revision 1.2Mar 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)61,8074
Polymers61,0202
Non-polymers7872
Water1,26170
1
A: Mitogen-activated protein kinase kinase kinase 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,9032
Polymers30,5101
Non-polymers3931
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)30,9032
Polymers30,5101
Non-polymers3931
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.544, 78.544, 434.028
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-8GY / 2-(6-{4-[(2R)-1-hydroxypropan-2-yl]-4H-1,2,4-triazol-3-yl}pyridin-2-yl)-6-[(propan-2-yl)oxy]-2,3-dihydro-1H-isoindol-1-one


Mass: 393.439 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H23N5O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 70 / 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 ,0.05M Ammonium Sulphate, 0.1M MES, pH 6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9789 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jun 28, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9789 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 28981 / % possible obs: 99.9 % / Redundancy: 10.4 % / Rmerge(I) obs: 0.082 / Rpim(I) all: 0.027 / Rrim(I) all: 0.087 / Χ2: 1.001 / Net I/σ(I): 6.4 / Num. measured all: 300861
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.5-2.549.90.6650.8760.2210.7020.983100
2.54-2.599.80.5370.9260.1780.5660.975100
2.59-2.6411.10.510.9420.160.5350.9999.8
2.64-2.6911.20.4320.9620.1350.4531.01899.8
2.69-2.75110.3530.9720.1110.3711.01299.9
2.75-2.8210.80.2980.9740.0940.3131.012100
2.82-2.8910.90.280.9830.0880.2941.014100
2.89-2.9610.60.2220.9880.0710.2331.015100
2.96-3.0510.40.1860.990.060.1951.017100
3.05-3.159.50.1490.9930.050.1580.994100
3.15-3.2610.80.1270.9960.040.1330.993100
3.26-3.39110.1120.9960.0350.1170.991100
3.39-3.5510.90.0920.9970.0290.0970.99100
3.55-3.7310.60.0850.9970.0270.0891.014100
3.73-3.9710.20.0730.9980.0240.0770.995100
3.97-4.279.70.0650.9980.0210.0690.989100
4.27-4.710.80.060.9980.0190.0631.004100
4.7-5.3810.40.0610.9980.0190.0641.0199.7
5.38-6.789.40.0610.9980.020.0640.99499.7
6.78-5090.0540.9980.0190.0571.00699.5

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
REFMAC5.7.0025refinement
PDB_EXTRACT3.22data extraction
DENZOdata reduction
SCALEPACKdata scaling
RefinementResolution: 2.5→30 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.906 / SU B: 19.145 / SU ML: 0.21 / SU R Cruickshank DPI: 0.3687 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.369 / ESU R Free: 0.253 / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.253 1468 5.1 %RANDOM
Rwork0.228 ---
obs0.2294 27373 99.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 199.63 Å2 / Biso mean: 76.267 Å2 / Biso min: 30.01 Å2
Baniso -1Baniso -2Baniso -3
1-2.15 Å21.08 Å20 Å2
2--2.15 Å20 Å2
3----3.23 Å2
Refinement stepCycle: final / Resolution: 2.5→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4097 0 58 70 4225
Biso mean--45.69 55.56 -
Num. residues----515
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0194251
X-RAY DIFFRACTIONr_angle_refined_deg1.1521.995735
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3545509
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.03624.607191
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.77415755
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.891518
X-RAY DIFFRACTIONr_chiral_restr0.0780.2610
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213202
LS refinement shellResolution: 2.5→2.565 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.456 104 -
Rwork0.343 1953 -
all-2057 -
obs--99.76 %
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)
13.509-0.91481.01450.30130.08734.77890.1392-0.0321-0.0543-0.10830.04220.09430.01720.0058-0.18140.3842-0.153-0.02680.13880.03710.3535-7.53911.42221.3235
21.95720.85221.49782.73263.35738.4856-0.12410.4523-0.1225-0.26450.3528-0.0974-0.08311.0977-0.22870.2415-0.15980.05410.3242-0.01260.27433.51393.697218.2112
32.99011.18560.05313.46382.572310.8645-0.17470.2055-0.10080.35740.3203-0.3308-0.12641.7196-0.14560.2088-0.20510.00430.4996-0.00080.30113.328512.134436.4646
41.97522.11850.17232.3785-0.673210.4631-0.09410.2893-0.2735-0.08850.2053-0.2684-0.22151.7715-0.11120.2054-0.19810.05220.4794-0.06870.235510.18598.95627.8508
50.1441-0.2540.41745.08912.41429.7743-0.25490.1772-0.125-1.04710.519-0.4172-1.97822.696-0.26410.8667-0.72330.20241.0224-0.11210.496716.095118.807221.4035
60.82390.90680.04276.46211.077612.2802-0.19460.18120.067-0.57540.5243-0.1074-2.29752.3851-0.32960.7528-0.76940.00630.7893-0.03570.417218.635124.930731.8573
73.9904-0.06850.62212.0028-0.57574.82140.2692-0.08950.12940.481-0.16340.0366-0.1376-0.615-0.10590.2668-0.04970.01940.14620.01330.160953.04694.598913.8335
82.9128-0.71341.11682.3692-0.46536.59710.0625-0.18340.28780.5102-0.07090.2826-0.8973-1.21790.00850.42270.11680.12440.48310.00810.327943.829313.221315.6952
91.11390.1246-0.83953.43640.76686.96650.43780.15970.2812-0.6087-0.35470.2793-1.9171-1.2918-0.08310.78320.52720.06660.39850.07650.328443.454922.9497-6.3587
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A671 - 704
2X-RAY DIFFRACTION2A705 - 768
3X-RAY DIFFRACTION3A769 - 796
4X-RAY DIFFRACTION4A797 - 820
5X-RAY DIFFRACTION5A821 - 876
6X-RAY DIFFRACTION6A877 - 939
7X-RAY DIFFRACTION7B670 - 704
8X-RAY DIFFRACTION8B705 - 755
9X-RAY DIFFRACTION9B756 - 939

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