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- PDB-7jv1: Crystal Structure of KSR1:MEK1 in complex with AMP-PNP, and allos... -

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Basic information

Entry
Database: PDB / ID: 7jv1
TitleCrystal Structure of KSR1:MEK1 in complex with AMP-PNP, and allosteric MEK inhibitor APS-9-95-1
Components
  • Dual specificity mitogen-activated protein kinase kinase 1
  • Kinase suppressor of Ras 1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / Pseudokinase / drug target / cell signaling and cancer / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


regulation of MAP kinase activity / JUN kinase kinase activity / mitogen-activated protein kinase kinase / MAP-kinase scaffold activity / regulation of Golgi inheritance / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / 14-3-3 protein binding / RAF activation / Signaling by high-kinase activity BRAF mutants ...regulation of MAP kinase activity / JUN kinase kinase activity / mitogen-activated protein kinase kinase / MAP-kinase scaffold activity / regulation of Golgi inheritance / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / 14-3-3 protein binding / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / ruffle membrane / Signaling by RAF1 mutants / Negative regulation of MAPK pathway / 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 / regulation of cell population proliferation / protein tyrosine kinase activity / Ras protein signal transduction / eukaryotic translation initiation factor 2alpha kinase activity / early endosome / 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 / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / protein kinase activity / positive regulation of MAPK cascade / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / intracellular membrane-bounded organelle / centrosome / endoplasmic reticulum membrane / endoplasmic reticulum / protein-containing complex / mitochondrion / zinc ion binding / ATP binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
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 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 / Chem-VKG / Dual specificity mitogen-activated protein kinase kinase 1 / Kinase suppressor of Ras 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Oryctolagus cuniculus (rabbit)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.62 Å
AuthorsKhan, Z.M. / Dar, A.C. / Scopton, A.P.
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 2.0Oct 7, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / entity ...atom_site / entity / entity_name_com / entity_poly / entity_poly_seq / entity_src_gen / pdbx_entity_nonpoly / pdbx_entry_details / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_assembly_gen / pdbx_struct_conn_angle / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_residues / pdbx_validate_polymer_linkage / pdbx_validate_torsion / struct_asym / struct_conf / struct_conn / struct_mon_prot_cis / struct_ref / struct_ref_seq / struct_ref_seq_dif / struct_sheet_range
Item: _atom_site.auth_asym_id / _atom_site.label_asym_id ..._atom_site.auth_asym_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _atom_site.label_seq_id / _entity_name_com.entity_id / _entity_poly_seq.entity_id / _entity_poly_seq.num / _pdbx_entity_nonpoly.entity_id / _pdbx_entry_details.compound_details / _pdbx_nonpoly_scheme.asym_id / _pdbx_nonpoly_scheme.entity_id / _pdbx_nonpoly_scheme.pdb_strand_id / _pdbx_poly_seq_scheme.asym_id / _pdbx_poly_seq_scheme.entity_id / _pdbx_poly_seq_scheme.ndb_seq_num / _pdbx_poly_seq_scheme.pdb_strand_id / _pdbx_poly_seq_scheme.seq_id / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_sheet_hbond.range_1_auth_asym_id / _pdbx_struct_sheet_hbond.range_1_label_asym_id / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_auth_asym_id / _pdbx_struct_sheet_hbond.range_2_label_asym_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _pdbx_unobs_or_zero_occ_residues.auth_asym_id / _pdbx_unobs_or_zero_occ_residues.label_asym_id / _pdbx_unobs_or_zero_occ_residues.label_seq_id / _pdbx_validate_torsion.auth_asym_id / _struct_conf.beg_auth_asym_id / _struct_conf.beg_label_asym_id / _struct_conf.beg_label_seq_id / _struct_conf.end_auth_asym_id / _struct_conf.end_label_asym_id / _struct_conf.end_label_seq_id / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_id / _struct_mon_prot_cis.auth_asym_id / _struct_mon_prot_cis.label_asym_id / _struct_mon_prot_cis.label_seq_id / _struct_mon_prot_cis.pdbx_auth_asym_id_2 / _struct_mon_prot_cis.pdbx_label_asym_id_2 / _struct_mon_prot_cis.pdbx_label_seq_id_2 / _struct_ref_seq_dif.align_id / _struct_ref_seq_dif.pdbx_pdb_strand_id / _struct_ref_seq_dif.seq_num / _struct_sheet_range.beg_auth_asym_id / _struct_sheet_range.beg_label_asym_id / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_auth_asym_id / _struct_sheet_range.end_label_asym_id / _struct_sheet_range.end_label_seq_id
Revision 2.1Dec 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 2.2Oct 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
Revision 2.3Dec 25, 2024Group: Advisory / Derived calculations / Structure summary
Category: pdbx_entry_details / pdbx_validate_close_contact ...pdbx_entry_details / pdbx_validate_close_contact / struct_conn / struct_conn_type
Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)83,4206
Polymers81,7172
Non-polymers1,7034
Water00
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 area6400 Å2
ΔGint-43 kcal/mol
Surface area28250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)137.000, 137.000, 221.000
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Space group name HallP612(x,y,z+5/12)

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Components

#1: Protein Kinase suppressor of Ras 1


Mass: 38597.137 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KSR1, KSR / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q8IVT5, 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
#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 / References: UniProt: P29678*PLUS / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-VKG / N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)-N'-methylsulfuric diamide


Mass: 666.463 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H24FIN6O5S / Feature type: SUBJECT OF INVESTIGATION
Compound detailsThe author states that kinase suppressor of Ras 1 chain B is proteolytically cleaved between Trp632 ...The author states that kinase suppressor of Ras 1 chain B is proteolytically cleaved between Trp632 and His633.
Has ligand of interestY
Has protein modificationN

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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: 3.66 Å3/Da / Density % sol: 66.42 %
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: Nov 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.62→49 Å / Num. obs: 13701 / % possible obs: 93.7 % / Redundancy: 12.55 % / Biso Wilson estimate: 165.31 Å2 / CC1/2: 1 / Net I/σ(I): 16.46
Reflection shellResolution: 3.62→3.71 Å / Num. unique obs: 1006 / CC1/2: 0.496

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Processing

Software
NameVersionClassification
PHENIX1.14rc1_3177refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2Y4I

2y4i


Resolution: 3.62→46.2 Å / SU ML: 0.5291 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 37.6037 / Stereochemistry target values: CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3033 679 4.96 %
Rwork0.2767 13018 -
obs0.2781 13697 93.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.62→46.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4639 0 102 0 4741
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00324848
X-RAY DIFFRACTIONf_angle_d0.87456554
X-RAY DIFFRACTIONf_chiral_restr0.0491709
X-RAY DIFFRACTIONf_plane_restr0.0051821
X-RAY DIFFRACTIONf_dihedral_angle_d9.26722891
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.62-3.90.39621340.35432552X-RAY DIFFRACTION94.81
3.9-4.290.34361310.31892583X-RAY DIFFRACTION94.73
4.29-4.910.37521270.31422590X-RAY DIFFRACTION94.11
4.91-6.180.33651390.31582588X-RAY DIFFRACTION93.42
6.18-46.20.25421480.23552705X-RAY DIFFRACTION91.53

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