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- PDB-7jus: Crystal Structure of KSR2:MEK1 in complex with AMP-PNP, and allos... -

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Basic information

Entry
Database: PDB / ID: 7jus
TitleCrystal Structure of KSR2:MEK1 in complex with AMP-PNP, and allosteric MEK inhibitor Cobimetinib
Components
  • Dual specificity mitogen-activated protein kinase kinase 1
  • Kinase suppressor of Ras 2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Pseudokinase / drug target / cell signaling and cancer / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


JUN kinase kinase activity / mitogen-activated protein kinase kinase / MAP-kinase scaffold activity / regulation of Golgi inheritance / mitogen-activated protein kinase kinase binding / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / calcium-mediated signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation ...JUN kinase kinase activity / mitogen-activated protein kinase kinase / MAP-kinase scaffold activity / regulation of Golgi inheritance / mitogen-activated protein kinase kinase binding / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / calcium-mediated signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by BRAF and RAF1 fusions / late endosome / positive regulation of cold-induced thermogenesis / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / Ras protein signal transduction / eukaryotic translation initiation factor 2alpha kinase activity / positive regulation of MAPK cascade / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / early endosome / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / protein kinase activity / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / centrosome / mitochondrion / ATP binding / nucleus / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Kinase suppressor of RAS, SAM-like domain / SAM like domain present in kinase suppressor RAS 1 / Kinase suppressor RAS 1, N-terminal helical hairpin / Kinase suppressor RAS 1, N-terminal helical hairpin superfamily / Kinase suppressor RAS 1 N-terminal helical hairpin / : / : / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) ...Kinase suppressor of RAS, SAM-like domain / SAM like domain present in kinase suppressor RAS 1 / Kinase suppressor RAS 1, N-terminal helical hairpin / Kinase suppressor RAS 1, N-terminal helical hairpin superfamily / Kinase suppressor RAS 1 N-terminal helical hairpin / : / : / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / Sterile alpha motif/pointed 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. / 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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / Cobimetinib / Dual specificity mitogen-activated protein kinase kinase 1 / Kinase suppressor of Ras 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Oryctolagus cuniculus (rabbit)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.99 Å
AuthorsKhan, Z.M. / Dar, A.C.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Center for Advancing Translational Sciences (NIH/NCATS)5R01CA227636-02 United States
National Institutes of Health/National Center for Advancing Translational Sciences (NIH/NCATS)1DP2CA186570-01 United States
CitationJournal: Nature / Year: 2020
Title: Structural basis for the action of the drug trametinib at KSR-bound MEK.
Authors: Khan, Z.M. / Real, A.M. / Marsiglia, W.M. / Chow, A. / Duffy, M.E. / Yerabolu, J.R. / Scopton, A.P. / Dar, A.C.
History
DepositionAug 20, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 30, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 30, 2020Group: 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
Revision 1.2Oct 18, 2023Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Kinase suppressor of Ras 2
C: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,4607
Polymers82,8682
Non-polymers1,5925
Water19811
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, The MEK1:KSR1 heterodimer was also eluted as a homo-dimer of MEK1:KSR1 heterodimer, centered around KSR1
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3990 Å2
ΔGint-35 kcal/mol
Surface area27680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)140.000, 140.000, 220.000
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

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Protein , 2 types, 2 molecules BC

#1: Protein Kinase suppressor of Ras 2 / hKSR2


Mass: 39748.730 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KSR2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q6VAB6, non-specific serine/threonine protein kinase
#2: Protein Dual specificity mitogen-activated protein kinase kinase 1 / MAPKK 1 / ERK activator kinase 1 / MAPK/ERK kinase 1 / MEK 1


Mass: 43119.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Oryctolagus cuniculus (rabbit) / Gene: MAP2K1, MEK1, PRKMK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P29678, mitogen-activated protein kinase kinase

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Non-polymers , 4 types, 16 molecules

#3: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-VKD / Cobimetinib / {3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}{3-hydroxy-3-[(2R)-piperidin-2-yl]azetidin-1-yl}methanone


Mass: 531.310 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21F3IN3O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, anticancer, inhibitor*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 11 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.76 Å3/Da / Density % sol: 67.25 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: PEG 2000, MES, pH 6.5, Magnesium acetate

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 1 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Jun 9, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.99→50 Å / Num. obs: 28132 / % possible obs: 99.9 % / Redundancy: 11.98 % / CC1/2: 1 / Net I/σ(I): 22.26
Reflection shellResolution: 2.99→3.07 Å / Num. unique obs: 25108 / CC1/2: 0.512

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Processing

Software
NameVersionClassification
PHENIX(1.14rc1_3177)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2Y4I

2y4i


Resolution: 2.99→46.724 Å / SU ML: 0.44 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 31.08 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2649 1382 4.91 %
Rwork0.2477 --
obs0.2486 28127 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.99→46.724 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4651 0 94 11 4756
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0134847
X-RAY DIFFRACTIONf_angle_d1.8136548
X-RAY DIFFRACTIONf_dihedral_angle_d10.1572914
X-RAY DIFFRACTIONf_chiral_restr0.112717
X-RAY DIFFRACTIONf_plane_restr0.011820
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.99-3.03110.36331160.35292608X-RAY DIFFRACTION99
3.0311-3.15250.36851320.34122611X-RAY DIFFRACTION100
3.1525-3.29590.35451270.30722632X-RAY DIFFRACTION100
3.2959-3.46960.36471450.31222623X-RAY DIFFRACTION100
3.4696-3.68690.29771440.28472653X-RAY DIFFRACTION100
3.6869-3.97150.28571480.26062613X-RAY DIFFRACTION100
3.9715-4.37090.26411570.2412666X-RAY DIFFRACTION100
4.3709-5.00270.24741360.22512698X-RAY DIFFRACTION100
5.0027-6.30041372728X-RAY DIFFRACTION100
6.3004-46.7240.22441400.21412913X-RAY DIFFRACTION100

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