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- PDB-5up3: Structure-Based Design of ASK1 Inhibitors as Potential First-in-C... -

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Basic information

Entry
Database: PDB / ID: 5up3
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 / 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-8GS / Mitogen-activated protein kinase kinase kinase 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.95 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)61,6594
Polymers61,0202
Non-polymers6392
Water362
1
A: Mitogen-activated protein kinase kinase kinase 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,8292
Polymers30,5101
Non-polymers3191
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)30,8292
Polymers30,5101
Non-polymers3191
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.790, 78.790, 431.367
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-8GS / 2-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-isoindol-1-one


Mass: 319.360 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H17N5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / 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: 61.17 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 7% polyethylene glycol 2000 MME , 0.05M Ammonium Sulphate, 0.05M MES, pH 6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: May 30, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.95→50 Å / Num. obs: 18017 / % possible obs: 100 % / Redundancy: 12.1 % / Rmerge(I) obs: 0.177 / Rpim(I) all: 0.054 / Rrim(I) all: 0.185 / Χ2: 1.021 / Net I/σ(I): 5 / Num. measured all: 218247
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.95-311.30.7868650.8920.2420.8230.999100
3-3.0612.20.7048810.8980.2090.7351.003100
3.06-3.1111.80.6118600.9330.1840.6390.99100
3.11-3.1812.50.5318600.9480.1550.5540.979100
3.18-3.2513.20.4668690.970.1330.4851.012100
3.25-3.3213.10.4228700.9750.120.4391.022100
3.32-3.4113.10.3518820.9810.10.3651.025100
3.41-3.5130.3168720.9770.0910.3291.053100
3.5-3.612.90.2858970.9820.0820.2971.031100
3.6-3.7211.90.2088520.9780.0640.2181.076100
3.72-3.8512.60.2498850.9830.0730.261.026100
3.85-412.30.2189010.9860.0640.2271.135100
4-4.1912.10.1788840.9850.0530.1861.021100
4.19-4.41110.1579100.990.050.1651.03100
4.41-4.6811.50.148890.9920.0440.1471.011100
4.68-5.0412.60.1349140.9940.0390.1390.995100
5.04-5.5512.70.1429150.9920.0420.1481.023100
5.55-6.3512.10.149380.9890.0420.1460.993100
6.35-811.10.129880.9940.0380.1260.998100
8-509.90.08810850.9980.030.0930.98799.7

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Processing

Software
NameVersionClassification
REFMAC5.7.0025refinement
HKL-2000data collection
HKL-2000data scaling
PDB_EXTRACT3.22data extraction
DENZOdata reduction
SCALEPACKdata scaling
RefinementResolution: 2.95→30 Å / Cor.coef. Fo:Fc: 0.891 / Cor.coef. Fo:Fc free: 0.876 / WRfactor Rfree: 0.2862 / WRfactor Rwork: 0.2305 / FOM work R set: 0.7697 / SU B: 38.297 / SU ML: 0.321 / SU R Cruickshank DPI: 1.5977 / SU Rfree: 0.4229 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 1.598 / ESU R Free: 0.423 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2888 913 5.1 %RANDOM
Rwork0.2417 ---
obs0.244 16956 99.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 205.48 Å2 / Biso mean: 79.935 Å2 / Biso min: 29.98 Å2
Baniso -1Baniso -2Baniso -3
1-2.11 Å21.06 Å20 Å2
2--2.11 Å20 Å2
3----3.17 Å2
Refinement stepCycle: final / Resolution: 2.95→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3981 0 48 2 4031
Biso mean--48.97 46.23 -
Num. residues----501
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0194120
X-RAY DIFFRACTIONr_angle_refined_deg1.3031.9875552
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8755493
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.80824.649185
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.80515735
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.4171517
X-RAY DIFFRACTIONr_chiral_restr0.0930.2590
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0213096
LS refinement shellResolution: 2.949→3.025 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.413 75 -
Rwork0.308 1215 -
all-1290 -
obs--99.61 %
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)
10.55610.50620.5950.55560.26961.8389-0.05660.151-0.0622-0.03790.12590.0455-0.06270.3574-0.06930.3859-0.11560.0450.3633-0.01250.35564.80195.965623.692
20.99711.46911.49722.21492.21322.2535-0.73060.54720.0136-0.89080.73440.1039-1.03880.8525-0.00380.9196-0.65270.13310.59330.0250.176217.164121.419423.4409
31.4294-0.5868-2.19473.4575-0.68415.10950.3238-0.5412-0.26520.1849-0.04670.8253-1.52541.6161-0.27710.7197-0.70460.20.7135-0.1260.276518.816924.497531.9193
48.5583.50022.42551.7266-0.01634.18350.0612-0.08880.04780.0441-0.0090.0258-0.2121-0.1592-0.05220.57770.13930.0240.28190.01070.325417.688766.084-14.8787
50.30440.2728-0.79660.2479-0.74262.5447-0.12260.0164-0.0618-0.08150.0275-0.0650.3457-0.43060.09510.4606-0.1101-0.05740.346800.36298.436456.6104-14.9473
61.11970.57861.90120.32470.98353.23070.0002-0.25160.0211-0.119-0.0730.0258-0.039-0.4450.07280.4767-0.1048-0.04120.3660.03310.33883.29957.8394-14.1488
70.31890.5585-0.13881.3036-0.42412.12220.07560.04060.11010.1545-0.1226-0.03010.212-0.23310.0470.3789-0.1626-0.05520.32560.03180.38634.152453.41663.523
83.7153-0.00721.70291.9156-1.18591.54780.26060.1735-0.0469-0.0236-0.00150.35090.3038-0.0128-0.2590.7491-0.3652-0.04050.20650.03750.23353.969839.63332.1826
91.0351-3.30220.148312.1477-2.66393.97930.48630.31060.0081-1.5128-0.66030.27590.6842-0.3870.1740.7327-0.03360.05270.21320.05430.390515.968734.42168.1824
100.43090.95380.79522.12881.88925.88090.5084-0.21580.03511.0563-0.4320.06991.8198-1.2507-0.07640.9628-0.6357-0.00760.48490.03980.0853-1.086341.419214.1575
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A670 - 842
2X-RAY DIFFRACTION2A843 - 876
3X-RAY DIFFRACTION3A877 - 940
4X-RAY DIFFRACTION4B671 - 684
5X-RAY DIFFRACTION5B685 - 731
6X-RAY DIFFRACTION6B732 - 755
7X-RAY DIFFRACTION7B756 - 825
8X-RAY DIFFRACTION8B826 - 876
9X-RAY DIFFRACTION9B877 - 897
10X-RAY DIFFRACTION10B898 - 939

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