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- PDB-9fpd: Crystal structure of human TAK1/TAB1 fusion protein in complex wi... -

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Basic information

Entry
Database: PDB / ID: 9fpd
TitleCrystal structure of human TAK1/TAB1 fusion protein in complex with compound S1
ComponentsMitogen-activated protein kinase kinase kinase 7,TGF-beta-activated kinase 1 and MAP3K7-binding protein 1
KeywordsTRANSFERASE / Inhibitor / Complex
Function / homology
Function and homology information


histone kinase activity / I-kappaB phosphorylation / nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / linear polyubiquitin binding / interleukin-17A-mediated signaling pathway / cardiac septum development / MAP kinase kinase kinase kinase activity / mitogen-activated protein kinase kinase kinase / interleukin-33-mediated signaling pathway / toll-like receptor 3 signaling pathway ...histone kinase activity / I-kappaB phosphorylation / nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / linear polyubiquitin binding / interleukin-17A-mediated signaling pathway / cardiac septum development / MAP kinase kinase kinase kinase activity / mitogen-activated protein kinase kinase kinase / interleukin-33-mediated signaling pathway / toll-like receptor 3 signaling pathway / type II transforming growth factor beta receptor binding / TRIF-dependent toll-like receptor signaling pathway / positive regulation of cGAS/STING signaling pathway / coronary vasculature development / ATAC complex / positive regulation of vascular associated smooth muscle cell migration / anoikis / non-canonical NF-kappaB signal transduction / interleukin-1-mediated signaling pathway / MyD88-dependent toll-like receptor signaling pathway / aorta development / toll-like receptor 4 signaling pathway / mitogen-activated protein kinase p38 binding / cytoplasmic pattern recognition receptor signaling pathway / p38MAPK cascade / stimulatory C-type lectin receptor signaling pathway / Fc-epsilon receptor signaling pathway / protein serine/threonine phosphatase activity / positive regulation of JUN kinase activity / positive regulation of macroautophagy / cellular response to angiotensin / MAP kinase activity / positive regulation of cell size / MAP kinase kinase kinase activity / canonical NF-kappaB signal transduction / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / TICAM1,TRAF6-dependent induction of TAK1 complex / heart morphogenesis / TRAF6-mediated induction of TAK1 complex within TLR4 complex / stress-activated MAPK cascade / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of cell cycle / JNK cascade / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / TNFR1-induced NF-kappa-B signaling pathway / positive regulation of interleukin-2 production / activated TAK1 mediates p38 MAPK activation / transforming growth factor beta receptor signaling pathway / protein serine/threonine kinase binding / protein serine/threonine kinase activator activity / Activation of NF-kappaB in B cells / NOD1/2 Signaling Pathway / TAK1-dependent IKK and NF-kappa-B activation / lung development / positive regulation of non-canonical NF-kappaB signal transduction / CLEC7A (Dectin-1) signaling / FCERI mediated NF-kB activation / positive regulation of T cell cytokine production / receptor tyrosine kinase binding / Interleukin-1 signaling / transcription coactivator binding / Downstream TCR signaling / MAPK cascade / cellular response to tumor necrosis factor / T cell receptor signaling pathway / Ca2+ pathway / scaffold protein binding / cellular response to hypoxia / molecular adaptor activity / DNA-binding transcription factor binding / in utero embryonic development / positive regulation of canonical NF-kappaB signal transduction / endosome membrane / Ub-specific processing proteases / positive regulation of MAPK cascade / defense response to bacterium / immune response / inflammatory response / negative regulation of gene expression / protein serine kinase activity / protein serine/threonine kinase activity / ubiquitin protein ligase binding / endoplasmic reticulum membrane / protein-containing complex binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / magnesium ion binding / endoplasmic reticulum / signal transduction / protein-containing complex / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / Protein phosphatase 2C / Protein phosphatase 2C family / Serine/threonine phosphatases, family 2C, catalytic domain / PPM-type phosphatase domain profile. / PPM-type phosphatase-like domain / PPM-type phosphatase-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Serine/threonine-protein kinase, active site ...: / Protein phosphatase 2C / Protein phosphatase 2C family / Serine/threonine phosphatases, family 2C, catalytic domain / PPM-type phosphatase domain profile. / PPM-type phosphatase-like domain / PPM-type phosphatase-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / 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
: / Mitogen-activated protein kinase kinase kinase 7 / TGF-beta-activated kinase 1 and MAP3K7-binding protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.402 Å
AuthorsScheufler, C. / Lammens, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Identification of TAK-756, A Potent TAK1 Inhibitor for the Treatment of Osteoarthritis through Intra-Articular Administration.
Authors: Langlois, J.B. / Brenneisen, S. / Rodde, S. / Vangrevelinghe, E. / Rose, G. / Lerch, P. / Sorge, M. / Ullrich, T. / Patora-Komisarska, K. / Quancard, J. / Larger, P. / Gianola, L. / Textor, ...Authors: Langlois, J.B. / Brenneisen, S. / Rodde, S. / Vangrevelinghe, E. / Rose, G. / Lerch, P. / Sorge, M. / Ullrich, T. / Patora-Komisarska, K. / Quancard, J. / Larger, P. / Gianola, L. / Textor, C. / Chenal, G. / Rubic-Schneider, T. / Simkova, K. / Masmanidou, O. / Scheufler, C. / Lammens, A. / Bouzan, A. / Demirci, S. / Flotte, L. / Rivet, H. / Hartmann, L. / Guezel, D. / Flueckiger, M. / Schilb, A. / Schuepbach, E. / Kettle, R. / Jacobi, C. / Pearson, D. / Richards, P.J. / Minetti, G.C.
History
DepositionJun 13, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 4, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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 7,TGF-beta-activated kinase 1 and MAP3K7-binding protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4185
Polymers35,8121
Non-polymers6064
Water57632
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area540 Å2
ΔGint8 kcal/mol
Surface area13990 Å2
Unit cell
Length a, b, c (Å)58.28, 133.755, 144.725
Angle α, β, γ (deg.)90, 90, 90
Int Tables number23
Space group name H-MI222

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Components

#1: Protein Mitogen-activated protein kinase kinase kinase 7,TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 / Transforming growth factor-beta-activated kinase 1 / TGF-beta-activated kinase 1 / Mitogen- ...Transforming growth factor-beta-activated kinase 1 / TGF-beta-activated kinase 1 / Mitogen-activated protein kinase kinase kinase 7-interacting protein 1 / TGF-beta-activated kinase 1-binding protein 1 / TAK1-binding protein 1


Mass: 35812.070 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: (AA1-AA6) - Cloning artifact (AA7-AA279) - UniProt O43318 (31-303) (AA280-AA316) - UniProt Q15750 (468-504),(AA1-AA6) - Cloning artifact (AA7-AA279) - UniProt O43318 (31-303) (AA280-AA316) - ...Details: (AA1-AA6) - Cloning artifact (AA7-AA279) - UniProt O43318 (31-303) (AA280-AA316) - UniProt Q15750 (468-504),(AA1-AA6) - Cloning artifact (AA7-AA279) - UniProt O43318 (31-303) (AA280-AA316) - UniProt Q15750 (468-504)
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP3K7, TAK1, TAB1, MAP3K7IP1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O43318, UniProt: Q15750, mitogen-activated protein kinase kinase kinase
#2: Chemical ChemComp-A1IED / 6-[5-[6-(4-oxidanylcyclohexyl)oxy-1~{H}-pyrrolo[2,3-b]pyridin-5-yl]-1,2-oxazol-3-yl]pyridine-2-carboxamide


Mass: 419.433 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H21N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 3.94 Å3/Da / Density % sol: 68.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Tris HCl pH 7.25, 0.9 M Tri-sodium citrate, 0.2 M sodium chloride, 10 mM DTT

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.000032 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.000032 Å / Relative weight: 1
ReflectionResolution: 2.354→98.2286 Å / Num. obs: 12956 / % possible obs: 54.2 % / Redundancy: 7.8 % / CC1/2: 0.998 / Rmerge(I) obs: 0.11 / Rpim(I) all: 0.042 / Rrim(I) all: 0.118 / Net I/av σ(I): 11.7 / Net I/σ(I): 11.7
Reflection shellResolution: 2.354→2.641 Å / Redundancy: 6.9 % / Rmerge(I) obs: 1.19 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 648 / CC1/2: 0.617 / % possible all: 9.4

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROCdata reduction
STARANISOdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.402→19.93 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.928 / SU R Cruickshank DPI: 0.541 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.538 / SU Rfree Blow DPI: 0.276 / SU Rfree Cruickshank DPI: 0.28
RfactorNum. reflection% reflectionSelection details
Rfree0.2224 621 -RANDOM
Rwork0.2079 ---
obs0.2086 12889 57.3 %-
Displacement parametersBiso mean: 81.36 Å2
Baniso -1Baniso -2Baniso -3
1--7.1222 Å20 Å20 Å2
2---3.9949 Å20 Å2
3---11.1171 Å2
Refine analyzeLuzzati coordinate error obs: 0.35 Å
Refinement stepCycle: LAST / Resolution: 2.402→19.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2392 0 43 32 2467
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0062504HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.753403HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d831SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes413HARMONIC5
X-RAY DIFFRACTIONt_it2469HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion308SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact1819SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.19
X-RAY DIFFRACTIONt_other_torsion16.45
LS refinement shellResolution: 2.402→2.59 Å
RfactorNum. reflection% reflection
Rfree0.3036 16 -
Rwork0.2826 --
obs--9.23 %
Refinement TLS params.

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)
100.2864-0.28150-1.50610.33210.00140.03810.04540.03810.0172-0.02690.0454-0.0269-0.01860.0481-0.0602-0.1338-0.09930.304-0.0831-14.9652-48.7669-17.0498
22.69820.7983-0.62613.3675-0.24070.9690.02870.34880.05650.3488-0.00660.08370.05650.0837-0.0221-0.17970.0362-0.0657-0.10870.12940.0882-6.4436-45.8987-27.0363
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ L|* }L1
2X-RAY DIFFRACTION2{ A|* }A26 - 496

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