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- PDB-7mu7: Ask1 bound to compound 3 -

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Basic information

Entry
Database: PDB / ID: 7mu7
TitleAsk1 bound to compound 3
ComponentsMitogen-activated protein kinase kinase kinase 5
KeywordsTRANSFERASE/INHIBITOR / ASK1 / 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 / Serine/threonine-protein kinase, active site ...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 / 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
Similarity search - Domain/homology
Chem-RFG / Mitogen-activated protein kinase kinase kinase 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.298 Å
AuthorsChodaparambil, J.V. / Marcotte, D.J.
CitationJournal: To Be Published
Title: Discovery of Potent, Selective and CNS-Penetrant Apoptosis Signal-regulating Kinase 1 (ASK1) Inhibitors that Modulate Brain Inflammation in Vivo
Authors: Chodaparambil, J.V.
History
DepositionMay 14, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 18, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)76,1128
Polymers75,0372
Non-polymers1,0756
Water1,08160
1
A: Mitogen-activated protein kinase kinase kinase 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0644
Polymers37,5181
Non-polymers5463
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Mitogen-activated protein kinase kinase kinase 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0484
Polymers37,5181
Non-polymers5303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)77.050, 77.050, 419.380
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11A-1140-

HOH

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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 / MEK kinase 5 / MEKK 5


Mass: 37518.453 Da / Num. of mol.: 2 / Fragment: kinase domain
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-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-RFG / 3-methoxy-N-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}-1-(pyrazin-2-yl)-1H-pyrazole-4-carboxamide


Mass: 405.413 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19N9O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 60 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.04 Å3/Da / Density % sol: 59.58 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.1M BisTRIS pH 5.5, 0.2M ammonium acetate, 3% sorbitol and 12% PEG3350

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.97 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 1, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.298→49 Å / Num. obs: 34330 / % possible obs: 99 % / Redundancy: 18.5 % / CC1/2: 0.99 / Rmerge(I) obs: 0.1 / Net I/σ(I): 21.87
Reflection shellResolution: 2.3→2.38 Å / Num. unique obs: 3290 / CC1/2: 0.66

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4bf2

4bf2


Resolution: 2.298→48.265 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 23.63 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2416 1716 5 %
Rwork0.2053 --
obs0.2071 34325 99.88 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.298→48.265 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3982 0 76 60 4118
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0054151
X-RAY DIFFRACTIONf_angle_d0.8455620
X-RAY DIFFRACTIONf_dihedral_angle_d4.9682956
X-RAY DIFFRACTIONf_chiral_restr0.058610
X-RAY DIFFRACTIONf_plane_restr0.005726
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.36540.33661370.28222595X-RAY DIFFRACTION99
2.3654-2.44170.30011390.27122642X-RAY DIFFRACTION100
2.4417-2.5290.34531390.26962636X-RAY DIFFRACTION100
2.529-2.63020.28991400.25112667X-RAY DIFFRACTION100
2.6302-2.74990.30431420.2312698X-RAY DIFFRACTION100
2.7499-2.89490.26441390.22862644X-RAY DIFFRACTION100
2.8949-3.07620.27281420.23292697X-RAY DIFFRACTION100
3.0762-3.31370.28841420.23622688X-RAY DIFFRACTION100
3.3137-3.64710.23051430.20362735X-RAY DIFFRACTION100
3.6471-4.17460.19241450.17632751X-RAY DIFFRACTION100
4.1746-5.25850.2131480.16282811X-RAY DIFFRACTION100
5.2585-48.2650.23431600.213045X-RAY DIFFRACTION100
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)
17.36614.2571-1.78472.6957-0.15813.48930.0704-0.0907-0.0460.180.0304-0.6488-0.07940.2959-0.05510.60310.1953-0.04760.4430.02310.40695.672.0904-19.513
24.863-2.8595-2.7187.65577.67168.4321-0.0639-0.0974-0.10460.61370.1934-0.0310.46170.4046-0.15010.73370.2410.07790.49660.11470.3961.5697-3.1941-20.3035
32.29442.06051.7089.3733-2.67333.66910.33-1.30440.52881.3116-0.21680.82340.0408-0.0969-0.06831.12730.29510.29280.91480.07240.7534-9.22513.625-9.3252
43.7690.7591-0.17993.4847-0.34182.55050.026-0.5647-0.4135-0.0829-0.06550.21920.47540.2644-0.02450.64590.17360.07220.43380.0580.5857-6.0602-1.5986-19.0396
53.8795-0.8347-0.30293.0199-1.48264.33150.0701-0.1602-0.05840.07250.0450.18180.16640.0548-0.10120.46240.11010.01650.3027-0.00230.4512-13.003410.4455-28.5985
62.4192-0.62560.25833.5045-0.66283.8363-0.0072-0.1757-0.0420.22530.13230.4203-0.3495-0.3842-0.10890.48640.17240.03680.4019-0.00280.5941-19.703622.3011-27.8826
74.5615-0.6821-5.90573.40590.35267.89110.078-0.2311-0.9709-0.3903-0.1763-0.0772-0.19810.19630.00430.68370.0992-0.01910.5892-0.05330.5082-55.93151.6566-15.5939
85.01870.60640.15812.20330.04675.6328-0.08610.25290.6528-0.8870.13910.0274-1.15890.1794-0.01570.8558-0.04020.06640.4133-0.0020.3977-48.439311.0415-14.5075
96.6950.86821.81326.82410.21474.7129-0.30560.98920.3683-1.44580.3172-0.0844-0.43160.4926-0.14460.8833-0.05470.14310.438-0.05290.5369-44.06739.7-13.1253
105.15631.8357-0.8237.1597-0.35496.70960.1021-0.08140.07290.05120.008-0.4752-0.23850.2065-0.0880.3968-0.03480.00640.2859-0.08310.4073-43.705114.98894.5829
114.6174-0.6947-2.43594.12753.2537.25680.3510.44870.4777-0.5586-0.225-0.1014-1.2952-0.1521-0.3390.7888-0.0438-0.00180.4318-0.03710.5966-43.984728.30940.4772
123.1421-0.4709-1.13668.34610.85526.14050.29990.12510.37630.17950.0156-0.0584-1.4161-0.2443-0.25790.90260.04060.06910.4828-0.13130.5201-46.116330.847311.8497
132.6137-0.2284-2.51137.8525-1.052.6563-0.0878-0.97860.09260.44330.0923-1.3665-0.24721.86770.1190.6617-0.045-0.23380.7663-0.13360.9097-32.350219.280813.384
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 671 through 699 )
2X-RAY DIFFRACTION2chain 'A' and (resid 700 through 712 )
3X-RAY DIFFRACTION3chain 'A' and (resid 713 through 731 )
4X-RAY DIFFRACTION4chain 'A' and (resid 732 through 758 )
5X-RAY DIFFRACTION5chain 'A' and (resid 759 through 842 )
6X-RAY DIFFRACTION6chain 'A' and (resid 843 through 940 )
7X-RAY DIFFRACTION7chain 'B' and (resid 669 through 684 )
8X-RAY DIFFRACTION8chain 'B' and (resid 685 through 731 )
9X-RAY DIFFRACTION9chain 'B' and (resid 732 through 758 )
10X-RAY DIFFRACTION10chain 'B' and (resid 759 through 820 )
11X-RAY DIFFRACTION11chain 'B' and (resid 821 through 876 )
12X-RAY DIFFRACTION12chain 'B' and (resid 877 through 928 )
13X-RAY DIFFRACTION13chain 'B' and (resid 929 through 940 )

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