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- PDB-3vw6: Crystal structure of human apoptosis signal-regulating kinase 1 (... -

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Basic information

Entry
Database: PDB / ID: 3vw6
TitleCrystal structure of human apoptosis signal-regulating kinase 1 (ASK1) with imidazopyridine inhibitor
ComponentsMitogen-activated protein kinase kinase kinase 5
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Transferase / 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 / JNK cascade / positive regulation of JUN kinase activity / 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-IM6 / Mitogen-activated protein kinase kinase kinase 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsTerao, Y. / Suzuki, H. / Yoshikawa, M. / Yashiro, H. / Takekawa, S. / Fujitani, Y. / Okada, K. / Inoue, Y. / Yamamoto, Y. / Nakagawa, H. ...Terao, Y. / Suzuki, H. / Yoshikawa, M. / Yashiro, H. / Takekawa, S. / Fujitani, Y. / Okada, K. / Inoue, Y. / Yamamoto, Y. / Nakagawa, H. / Yao, S. / Kawamoto, T. / Uchikawa, O.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2012
Title: Design and biological evaluation of imidazo[1,2-a]pyridines as novel and potent ASK1 inhibitors.
Authors: Terao, Y. / Suzuki, H. / Yoshikawa, M. / Yashiro, H. / Takekawa, S. / Fujitani, Y. / Okada, K. / Inoue, Y. / Yamamoto, Y. / Nakagawa, H. / Yao, S. / Kawamoto, T. / Uchikawa, O.
History
DepositionAug 6, 2012Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 31, 2012Provider: repository / Type: Initial release
Revision 1.1Dec 20, 2017Group: Database references / Category: citation
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)61,3144
Polymers60,5952
Non-polymers7192
Water2,504139
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1120 Å2
ΔGint-11 kcal/mol
Surface area23630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.032, 78.032, 425.295
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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 / MEK kinase 5 / MEKK 5


Mass: 30297.613 Da / Num. of mol.: 2 / Fragment: kinase domain, UNP RESIDUES 671-939
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-IM6 / 4-tert-butyl-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamide


Mass: 359.424 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H21N5O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 139 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 3.08 Å3/Da / Density % sol: 60.12 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 10% PEG 6000, 1M lithium chloride, 0.1M HEPES, pH 7.0, VAPOR DIFFUSION, SITTING DROP, temperature 277.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 1 Å
DetectorDetector: CCD / Date: Aug 27, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionHighest resolution: 2.4 Å / Num. obs: 31268 / % possible obs: 98.5 % / Observed criterion σ(I): 2

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Processing

SoftwareName: REFMAC / Version: 5.5.0109 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→70.88 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.903 / SU B: 13.586 / SU ML: 0.15 / Cross valid method: THROUGHOUT / ESU R: 0.304 / ESU R Free: 0.234 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25178 1569 5.1 %RANDOM
Rwork0.21273 ---
obs0.21472 29403 97.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 35.322 Å2
Baniso -1Baniso -2Baniso -3
1-0.35 Å20.18 Å20 Å2
2--0.35 Å20 Å2
3----0.53 Å2
Refinement stepCycle: LAST / Resolution: 2.4→70.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4014 0 54 139 4207
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0224174
X-RAY DIFFRACTIONr_bond_other_d0.0010.022873
X-RAY DIFFRACTIONr_angle_refined_deg1.2861.9935636
X-RAY DIFFRACTIONr_angle_other_deg0.86537026
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2735504
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.45424.892186
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.83415738
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.2041515
X-RAY DIFFRACTIONr_chiral_restr0.0720.2597
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0214595
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02824
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.461.52519
X-RAY DIFFRACTIONr_mcbond_other0.0771.51035
X-RAY DIFFRACTIONr_mcangle_it0.91724047
X-RAY DIFFRACTIONr_scbond_it1.45531655
X-RAY DIFFRACTIONr_scangle_it2.464.51588
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.396→2.458 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.307 91 -
Rwork0.282 1774 -
obs--81.62 %
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)
12.09781.63660.25593.05360.10381.1549-0.11460.2421-0.0105-0.18180.0984-0.10350.01970.03260.01620.089-0.04460.01870.05140.00610.04210.910712.204225.4564
21.29630.6379-0.67593.8956-1.87012.77560.00640.0524-0.2684-0.34750.09250.00960.4575-0.084-0.0990.1715-0.0223-0.0630.09350.05490.16026.137948.7123-0.4626
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A671 - 939
2X-RAY DIFFRACTION2B671 - 939

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