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- PDB-7umb: NanoBRET tracer Tram-bo bound to a KSR2-MEK1 complex -

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Basic information

Entry
Database: PDB / ID: 7umb
TitleNanoBRET tracer Tram-bo bound to a KSR2-MEK1 complex
Components
  • Dual specificity mitogen-activated protein kinase kinase 1
  • Kinase suppressor of Ras 2
KeywordsTRANSFERASE / Tracer / kinase / complex / MEK1 / KSR2
Function / homology
Function and homology information


epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / JUN kinase kinase activity / regulation of axon regeneration / mitogen-activated protein kinase kinase / placenta blood vessel development / MAP-kinase scaffold activity / labyrinthine layer development / cerebellar cortex formation / type B pancreatic cell proliferation ...epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / JUN kinase kinase activity / regulation of axon regeneration / mitogen-activated protein kinase kinase / placenta blood vessel development / MAP-kinase scaffold activity / labyrinthine layer development / cerebellar cortex formation / type B pancreatic cell proliferation / Signaling by MAP2K mutants / positive regulation of axonogenesis / regulation of Golgi inheritance / trachea formation / mitogen-activated protein kinase kinase binding / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / MAPK3 (ERK1) activation / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / endodermal cell differentiation / face development / MAP kinase kinase activity / Bergmann glial cell differentiation / Uptake and function of anthrax toxins / thyroid gland development / protein kinase activator activity / positive regulation of protein serine/threonine kinase activity / Schwann cell development / keratinocyte differentiation / myelination / ERK1 and ERK2 cascade / protein serine/threonine/tyrosine kinase activity / insulin-like growth factor receptor signaling pathway / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / thymus development / Signal transduction by L1 / cell motility / RAF activation / calcium-mediated signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / neuron differentiation / chemotaxis / 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 / cellular senescence / Signaling by BRAF and RAF1 fusions / MAPK cascade / late endosome / positive regulation of cold-induced thermogenesis / heart development / protein tyrosine kinase activity / scaffold protein binding / 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 / positive regulation of ERK1 and ERK2 cascade / non-specific serine/threonine protein kinase / protein kinase activity / positive regulation of MAPK cascade / ciliary basal body / negative regulation of cell population proliferation / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / intracellular membrane-bounded organelle / centrosome / positive regulation of gene expression / positive regulation of DNA-templated transcription / endoplasmic reticulum / Golgi apparatus / signal transduction / mitochondrion / zinc ion binding / ATP binding / nucleus
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 / Chem-U9F / Dual specificity mitogen-activated protein kinase kinase 1 / Kinase suppressor of Ras 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.231 Å
AuthorsMarsiglia, W.M. / Khan, K.M. / Dar, A.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Nat.Chem.Biol. / Year: 2024
Title: Live-cell target engagement of allosteric MEKi on MEK-RAF/KSR-14-3-3 complexes.
Authors: Marsiglia, W.M. / Chow, A. / Khan, Z.M. / He, L. / Dar, A.C.
History
DepositionApr 6, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 27, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: 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
Revision 1.2Mar 20, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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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)84,9245
Polymers82,8682
Non-polymers2,0563
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4070 Å2
ΔGint-14 kcal/mol
Surface area28000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)139.500, 139.500, 220.000
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)
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/6
#3: y,-x+y,z+5/6
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+2/3
#8: -x,-y,z+1/2
#9: y,x,-z+1/3
#10: -y,-x,-z+5/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+1/6

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Components

#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


Mass: 43119.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q02750
#3: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Comment: AMP-PNP, energy-carrying molecule analogue*YM
#4: Chemical ChemComp-U9F / {3-[(1M,2M)-2-{[(1S,2P)-1H,1'H-[2,2'-bipyrrol]-5-yl-kappaN~1~]methylidene}-2H-pyrrol-5-yl-kappaN]-N-(2-{2-[3-({(3M)-3-[(4aM)-3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl}amino)-3-oxopropoxy]ethoxy}ethyl)propanamidato}(difluorido)boron


Mass: 1043.635 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C47H46BF3IN9O7 / Feature type: SUBJECT OF INVESTIGATION
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: 3.73 Å3/Da / Density % sol: 67.01 %
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: NSLS-II / Beamline: 17-ID-1 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Dec 6, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.231→29.71 Å / Num. obs: 20907 / % possible obs: 99 % / Redundancy: 20.6 % / Biso Wilson estimate: 129.14 Å2 / CC1/2: 0.492 / Rrim(I) all: 0.166 / Net I/σ(I): 13.86
Reflection shellResolution: 3.231→3.31 Å / Num. unique obs: 1508 / CC1/2: 0.492 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2Y4I

2y4i


Resolution: 3.231→29.71 Å / SU ML: 0.4959 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 28.6203
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2683 1076 5.15 %
Rwork0.2285 19831 -
obs0.2306 20907 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 128.04 Å2
Refinement stepCycle: LAST / Resolution: 3.231→29.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4651 0 130 0 4781
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01174889
X-RAY DIFFRACTIONf_angle_d1.4016609
X-RAY DIFFRACTIONf_chiral_restr0.0699716
X-RAY DIFFRACTIONf_plane_restr0.012825
X-RAY DIFFRACTIONf_dihedral_angle_d12.6801656
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.231-3.380.37911300.33422414X-RAY DIFFRACTION99.76
3.38-3.560.34621190.28762437X-RAY DIFFRACTION100
3.56-3.780.30751420.26312431X-RAY DIFFRACTION99.96
3.78-4.070.31381250.24322433X-RAY DIFFRACTION100
4.07-4.480.25591510.22572444X-RAY DIFFRACTION100
4.48-5.120.27511430.21652471X-RAY DIFFRACTION100
5.12-6.440.25841380.25122512X-RAY DIFFRACTION100
6.44-29.710.23731280.19822689X-RAY DIFFRACTION99.89

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