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- PDB-6yg3: Crystal structure of MKK7 (MAP2K7) covalently bound with CPT1-70-1 -

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Basic information

Entry
Database: PDB / ID: 6yg3
TitleCrystal structure of MKK7 (MAP2K7) covalently bound with CPT1-70-1
ComponentsDual specificity mitogen-activated protein kinase kinase 7
KeywordsTRANSFERASE / kinase / kinase inhibitor / MKK7 / MEK7 / MAP2K7 / MAP2K / MEK / JNK signaling / Structural Genomics / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


JUN kinase kinase activity / regulation of motor neuron apoptotic process / mitogen-activated protein kinase kinase / response to osmotic stress / Fc-epsilon receptor signaling pathway / positive regulation of telomere maintenance / response to tumor necrosis factor / MAP kinase kinase activity / Uptake and function of anthrax toxins / MAP kinase activity ...JUN kinase kinase activity / regulation of motor neuron apoptotic process / mitogen-activated protein kinase kinase / response to osmotic stress / Fc-epsilon receptor signaling pathway / positive regulation of telomere maintenance / response to tumor necrosis factor / MAP kinase kinase activity / Uptake and function of anthrax toxins / MAP kinase activity / cellular response to interleukin-1 / stress-activated MAPK cascade / response to UV / JNK cascade / molecular function activator activity / JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 / positive regulation of JNK cascade / FCERI mediated MAPK activation / response to wounding / cellular senescence / cellular response to lipopolysaccharide / response to heat / protein tyrosine kinase activity / protein phosphatase binding / Oxidative Stress Induced Senescence / positive regulation of ERK1 and ERK2 cascade / protein serine kinase activity / apoptotic process / protein kinase binding / positive regulation of DNA-templated transcription / enzyme binding / magnesium ion binding / signal transduction / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
: / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 domain profile. ...: / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-6HF / Dual specificity mitogen-activated protein kinase kinase 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsChaikuad, A. / Tan, L. / Wang, J. / Liang, Y. / Gray, N.S. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Cell Chem Biol / Year: 2020
Title: Catalytic Domain Plasticity of MKK7 Reveals Structural Mechanisms of Allosteric Activation and Diverse Targeting Opportunities.
Authors: Schroder, M. / Tan, L. / Wang, J. / Liang, Y. / Gray, N.S. / Knapp, S. / Chaikuad, A.
History
DepositionMar 27, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 12, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 2, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 28, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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 7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,97311
Polymers34,9451
Non-polymers1,02810
Water2,108117
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1800 Å2
ΔGint23 kcal/mol
Surface area13790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.170, 64.490, 85.500
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Dual specificity mitogen-activated protein kinase kinase 7 / MAPKK 7 / JNK-activating kinase 2 / MAPK/ERK kinase 7 / MEK 7 / Stress-activated protein kinase ...MAPKK 7 / JNK-activating kinase 2 / MAPK/ERK kinase 7 / MEK 7 / Stress-activated protein kinase kinase 4 / SAPKK4 / c-Jun N-terminal kinase kinase 2 / JNKK 2


Mass: 34944.621 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K7, JNKK2, MEK7, MKK7, PRKMK7, SKK4 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): -R3-pRARE2
References: UniProt: O14733, mitogen-activated protein kinase kinase
#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-6HF / N-(4-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide / CPT-1691 / N-{4-[(2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]phenyl}prop-2-enamide


Mass: 469.538 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H27N7O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 117 / 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: 2.29 Å3/Da / Density % sol: 46.4 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 8.2
Details: 19% PEG3350, 0.25 M ammonium acetate, 0.1 M tris, pH 8.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 13, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.05→30.385 Å / Num. obs: 20596 / % possible obs: 99.1 % / Redundancy: 6.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.098 / Rpim(I) all: 0.041 / Rrim(I) all: 0.107 / Net I/av σ(I): 5.9 / Net I/σ(I): 10.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allRsym value% possible all
2.05-2.166.60.9350.829300.4940.3871.0140.93598.4
2.16-2.296.70.6281.227970.2580.6810.62898.9
2.29-2.456.50.4261.826230.1780.4630.42699
2.45-2.656.50.2832.724730.1180.3080.28399
2.65-2.96.90.193.922780.0770.2060.1999.2
2.9-3.246.70.1245.720790.0510.1340.12499.3
3.24-3.746.70.0758.618380.0310.0810.07599.7
3.74-4.586.50.05810.415880.0240.0630.05899.7
4.58-6.486.50.05311.312590.0220.0580.05399.6
6.48-30.38560.0318.67310.0130.0330.0398.7

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Processing

Software
NameVersionClassification
SCALA3.3.21data scaling
REFMAC5.8.0073refinement
PDB_EXTRACT3.25data extraction
iMOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2dyl

2dyl


Resolution: 2.05→30.38 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.938 / SU B: 10.942 / SU ML: 0.145 / SU R Cruickshank DPI: 0.1869 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.187 / ESU R Free: 0.169
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2351 1032 5 %RANDOM
Rwork0.1884 ---
obs0.1908 19531 98.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 109.27 Å2 / Biso mean: 44.495 Å2 / Biso min: 25.2 Å2
Baniso -1Baniso -2Baniso -3
1--1.01 Å2-0 Å2-0 Å2
2--0.05 Å2-0 Å2
3---0.96 Å2
Refinement stepCycle: final / Resolution: 2.05→30.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2107 0 70 117 2294
Biso mean--50.03 50.27 -
Num. residues----265
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0192231
X-RAY DIFFRACTIONr_bond_other_d0.0010.022204
X-RAY DIFFRACTIONr_angle_refined_deg1.5191.972983
X-RAY DIFFRACTIONr_angle_other_deg0.77635078
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9765269
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.26124.04394
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.18615419
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.7051513
X-RAY DIFFRACTIONr_chiral_restr0.0870.2321
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022575
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02496
LS refinement shellResolution: 2.05→2.103 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.284 73 -
Rwork0.29 1419 -
all-1492 -
obs--98.09 %
Refinement TLS params.

S22: 0.0259 Å ° / 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 °)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)
13.1188-0.50040.18690.59980.0341.6514-0.0797-0.15840.26260.06290.0242-0.27220.0160.05380.2230.01130.03060.1141-0.01860.0707-0.98333.1224.937
20.3729-0.33470.63831.463-0.34251.4013-0.04440.0025-0.04380.04280.0839-0.12410.02550.01860.1227-0.02360.02060.1394-0.00980.042219.14619.83215.605
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A119 - 216
2X-RAY DIFFRACTION2A217 - 416

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