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- PDB-5kkr: KSR2:MEK1 Complex Bound to the Small Molecule APS-2-79 -

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Basic information

Entry
Database: PDB / ID: 5kkr
TitleKSR2:MEK1 Complex Bound to the Small Molecule APS-2-79
Components
  • Dual specificity mitogen-activated protein kinase kinase 1
  • Kinase suppressor of Ras 2
KeywordsTRANSFERASE / Kinase Suppressor of Ras Small Molecule Complex
Function / homology
Function and homology information


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 / MAP kinase kinase activity / calcium-mediated signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation ...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 / MAP kinase kinase activity / 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 / protein tyrosine kinase activity / Ras protein signal transduction / positive regulation of MAPK cascade / early endosome / non-specific serine/threonine protein kinase / protein kinase activity / phosphorylation / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / centrosome / mitochondrion / ATP binding / membrane / nucleus / metal ion binding / plasma membrane / cytoplasm / cytosol
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) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily ...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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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-6U7 / 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: 3.509 Å
AuthorsDhawan, N.S. / Scopton, A.P. / Dar, A.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)DP2 CA 186570-01 United States
CitationJournal: Nature / Year: 2016
Title: Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling.
Authors: Dhawan, N.S. / Scopton, A.P. / Dar, A.C.
History
DepositionJun 22, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 14, 2016Group: Database references
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Sep 27, 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)80,7983
Polymers80,4112
Non-polymers3871
Water00
1
B: Kinase suppressor of Ras 2
C: Dual specificity mitogen-activated protein kinase kinase 1
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)161,5966
Polymers160,8214
Non-polymers7752
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation10_554-y,-x,-z-1/61
2


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1940 Å2
ΔGint-13 kcal/mol
Surface area28730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)139.680, 139.680, 221.730
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein Kinase suppressor of Ras 2 / hKSR2


Mass: 36774.555 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: 43636.090 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
#3: Chemical ChemComp-6U7 / 6,7-dimethoxy-~{N}-(2-methyl-4-phenoxy-phenyl)quinazolin-4-amine


Mass: 387.431 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21N3O3

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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: 3.88 Å3/Da / Density % sol: 68.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.25
Details: 12% PEG-3350 100mM Bis-Tris 200mM Sodium Citrate 10mM Magnesium Acetate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.033 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 1, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 3.5→46.808 Å / Num. obs: 16616 / % possible obs: 99.9 % / Redundancy: 14.4 % / Net I/σ(I): 18.3

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2Y4I

2y4i


Resolution: 3.509→46.808 Å / SU ML: 0.43 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 30.76 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2874 839 5.06 %Random selection
Rwork0.25 ---
obs0.2519 16567 99.57 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.509→46.808 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4611 0 29 0 4640
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024738
X-RAY DIFFRACTIONf_angle_d0.5826385
X-RAY DIFFRACTIONf_dihedral_angle_d12.4351784
X-RAY DIFFRACTIONf_chiral_restr0.021700
X-RAY DIFFRACTIONf_plane_restr0.004811
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.5089-3.72860.2831280.31552494X-RAY DIFFRACTION97
3.7286-4.01640.33241560.28432555X-RAY DIFFRACTION100
4.0164-4.42030.31711570.26192561X-RAY DIFFRACTION100
4.4203-5.05920.29851290.25992630X-RAY DIFFRACTION100
5.0592-6.37160.28861170.29242677X-RAY DIFFRACTION100
6.3716-46.8120.26461520.21022811X-RAY DIFFRACTION100
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)
17.64071.23731.14968.9389-0.25953.1312-0.23990.79250.5245-0.39970.13270.44760.2911-0.54270.04340.9570.0589-0.19381.0943-0.15580.7897-68.669854.339-18.5683
25.99642.23992.86343.38671.8825.48940.6013-0.4949-1.07660.5684-0.1598-0.61590.46010.0219-0.4110.8050.0993-0.27830.9754-0.03470.9671-53.478648.16891.0345
36.93950.4847-2.57166.8426-1.71812.3650.14840.3692.6906-0.31050.43933.2641-1.014-0.2999-0.50091.09780.1999-0.15571.7191-0.27642.5265-61.974286.212512.2371
45.56351.96340.3276.92491.55273.9107-0.1602-0.17780.7671-0.0524-0.1260.6106-0.18-0.34140.25470.9267-0.0384-0.11091.2257-0.17881.1469-37.872780.194910.8849
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'B' and (resid 650 through 744 )
2X-RAY DIFFRACTION2chain 'B' and (resid 745 through 932 )
3X-RAY DIFFRACTION3chain 'C' and (resid 41 through 148 )
4X-RAY DIFFRACTION4chain 'C' and (resid 149 through 381 )

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