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- PDB-8p7j: Crystal structure of MAP2K6 with a covalent compound GCL96 -

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Basic information

Entry
Database: PDB / ID: 8p7j
TitleCrystal structure of MAP2K6 with a covalent compound GCL96
ComponentsDual specificity mitogen-activated protein kinase kinase 6
KeywordsTRANSFERASE / Kinase / Covalent / inhibitor / MAP2K6
Function / homology
Function and homology information


nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / mitogen-activated protein kinase kinase / stress-activated protein kinase signaling cascade / negative regulation of cold-induced thermogenesis / Myogenesis / PI5P Regulates TP53 Acetylation / p38MAPK cascade / MAP kinase kinase activity / Uptake and function of anthrax toxins / signal transduction in response to DNA damage ...nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / mitogen-activated protein kinase kinase / stress-activated protein kinase signaling cascade / negative regulation of cold-induced thermogenesis / Myogenesis / PI5P Regulates TP53 Acetylation / p38MAPK cascade / MAP kinase kinase activity / Uptake and function of anthrax toxins / signal transduction in response to DNA damage / stress-activated MAPK cascade / cardiac muscle contraction / activated TAK1 mediates p38 MAPK activation / regulation of signal transduction by p53 class mediator / NOD1/2 Signaling Pathway / bone development / PKR-mediated signaling / Interleukin-1 signaling / osteoblast differentiation / cellular senescence / MAPK cascade / Oxidative Stress Induced Senescence / protein tyrosine kinase activity / cytoskeleton / regulation of cell cycle / positive regulation of MAPK cascade / protein serine kinase activity / protein serine/threonine kinase activity / apoptotic process / protein kinase binding / signal transduction / nucleoplasm / ATP binding / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 ...Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-X3K / Dual specificity mitogen-activated protein kinase kinase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsWang, G.Q. / Seidler, N. / Roehm, S. / Gehringer, M. / Knapp, S. / Structural Genomics Consortium (SGC)
Funding support Canada, 1items
OrganizationGrant numberCountry
The Structural Genomics Consortium (SGC) Canada
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2025
Title: Probing the Protein Kinases' Cysteinome by Covalent Fragments.
Authors: Wang, G. / Seidler, N.J. / Rohm, S. / Pan, Y. / Liang, X.J. / Haarer, L. / Berger, B.T. / Sivashanmugam, S.A. / Wydra, V.R. / Forster, M. / Laufer, S.A. / Chaikuad, A. / Gehringer, M. / Knapp, S.
History
DepositionMay 30, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 5, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2023Group: Database references / Category: struct_ref_seq_dif / Item: _struct_ref_seq_dif.details
Revision 1.2Nov 13, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature
Item: _pdbx_entry_details.has_protein_modification
Revision 1.3Jan 8, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.4Feb 26, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Dual specificity mitogen-activated protein kinase kinase 6
B: Dual specificity mitogen-activated protein kinase kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,0264
Polymers65,5002
Non-polymers5272
Water63135
1
A: Dual specificity mitogen-activated protein kinase kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0132
Polymers32,7501
Non-polymers2631
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Dual specificity mitogen-activated protein kinase kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,0132
Polymers32,7501
Non-polymers2631
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.712, 96.920, 104.806
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP22121

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Components

#1: Protein Dual specificity mitogen-activated protein kinase kinase 6 / MAP kinase kinase 6 / MAPKK 6 / MAPK/ERK kinase 6 / MEK 6 / Stress-activated protein kinase kinase ...MAP kinase kinase 6 / MAPKK 6 / MAPK/ERK kinase 6 / MEK 6 / Stress-activated protein kinase kinase 3 / SAPK kinase 3 / SAPKK-3 / SAPKK3


Mass: 32749.885 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K6, MEK6, MKK6, PRKMK6, SKK3 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P52564, mitogen-activated protein kinase kinase
#2: Chemical ChemComp-X3K / N-[3-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]prop-2-enamide / N-(3-(1h-pyrrolo[2,3-B]pyridin-4-yl)phenyl)acrylamide


Mass: 263.294 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H13N3O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 35 / 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: 2.57 Å3/Da / Density % sol: 52.18 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: 0.05M magnesium chloride -- 30% PEG500MME -- 0.1M HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00003 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 1, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 2.4→48.72 Å / Num. obs: 27286 / % possible obs: 100 % / Redundancy: 13.5 % / CC1/2: 0.999 / Net I/σ(I): 14.6
Reflection shellResolution: 2.4→2.49 Å / Num. unique obs: 2822 / CC1/2: 0.71

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Processing

Software
NameVersionClassification
REFMAC5.8.0411refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→48.72 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.928 / SU B: 8.778 / SU ML: 0.199 / Cross valid method: THROUGHOUT / ESU R: 0.36 / ESU R Free: 0.262 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25744 1287 4.7 %RANDOM
Rwork0.19557 ---
obs0.19853 25961 99.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 55.382 Å2
Baniso -1Baniso -2Baniso -3
1--1.89 Å20 Å20 Å2
2--1.88 Å20 Å2
3---0.01 Å2
Refinement stepCycle: 1 / Resolution: 2.4→48.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4407 0 0 35 4442
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0124570
X-RAY DIFFRACTIONr_bond_other_d0.0010.0164423
X-RAY DIFFRACTIONr_angle_refined_deg1.671.6456178
X-RAY DIFFRACTIONr_angle_other_deg0.5531.57110227
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.425563
X-RAY DIFFRACTIONr_dihedral_angle_2_deg19.3866.11127
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.32610830
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0770.2695
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.025194
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02976
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_it5.5595.4042261
X-RAY DIFFRACTIONr_mcbond_other5.5585.4022260
X-RAY DIFFRACTIONr_mcangle_it7.9449.6982821
X-RAY DIFFRACTIONr_mcangle_other7.9439.6992822
X-RAY DIFFRACTIONr_scbond_it6.4535.8452309
X-RAY DIFFRACTIONr_scbond_other6.4515.8452310
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other9.28410.5063358
X-RAY DIFFRACTIONr_long_range_B_refined11.56852.45136
X-RAY DIFFRACTIONr_long_range_B_other11.56852.45135
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.359 85 -
Rwork0.272 1891 -
obs--99.8 %

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