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- PDB-6bxy: Menin in complex with MI-1481 -

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Basic information

Entry
Database: PDB / ID: 6bxy
TitleMenin in complex with MI-1481
ComponentsMenin
KeywordsProtein Binding / Transcription / inhibitor
Function / homology
Function and homology information


Y-form DNA binding / negative regulation of telomerase activity / negative regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of JNK cascade / MLL1/2 complex / T-helper 2 cell differentiation / osteoblast development / histone methyltransferase complex / Formation of WDR5-containing histone-modifying complexes / positive regulation of transforming growth factor beta receptor signaling pathway ...Y-form DNA binding / negative regulation of telomerase activity / negative regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of JNK cascade / MLL1/2 complex / T-helper 2 cell differentiation / osteoblast development / histone methyltransferase complex / Formation of WDR5-containing histone-modifying complexes / positive regulation of transforming growth factor beta receptor signaling pathway / MLL1 complex / R-SMAD binding / cleavage furrow / negative regulation of cell cycle / RHO GTPases activate IQGAPs / negative regulation of osteoblast differentiation / four-way junction DNA binding / response to UV / transcription initiation-coupled chromatin remodeling / transcription repressor complex / negative regulation of protein phosphorylation / Deactivation of the beta-catenin transactivating complex / Post-translational protein phosphorylation / response to gamma radiation / phosphoprotein binding / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Formation of the beta-catenin:TCF transactivating complex / negative regulation of DNA-binding transcription factor activity / nuclear matrix / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / MAPK cascade / protein-macromolecule adaptor activity / double-stranded DNA binding / chromosome, telomeric region / transcription cis-regulatory region binding / endoplasmic reticulum lumen / negative regulation of cell population proliferation / DNA repair / negative regulation of DNA-templated transcription / DNA damage response / chromatin binding / chromatin / regulation of transcription by RNA polymerase II / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.82 Å
AuthorsBorkin, D. / Klossowski, S. / Pollock, J. / Linhares, B. / Cierpicki, T. / Grembecka, J.
CitationJournal: J.Med.Chem. / Year: 2018
Title: Complexity of Blocking Bivalent Protein-Protein Interactions: Development of a Highly Potent Inhibitor of the Menin-Mixed-Lineage Leukemia Interaction.
Authors: Borkin, D. / Klossowski, S. / Pollock, J. / Miao, H. / Linhares, B.M. / Kempinska, K. / Jin, Z. / Purohit, T. / Wen, B. / He, M. / Sun, D. / Cierpicki, T. / Grembecka, J.
History
DepositionDec 19, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 28, 2018Provider: repository / Type: Initial release
Revision 1.1Jun 12, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 4, 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
A: Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,14111
Polymers54,5701
Non-polymers1,57110
Water5,188288
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry, Fluorescence polarization anisotropy assay
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.319, 80.539, 122.341
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Menin


Mass: 54570.223 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MEN1, SCG2 / Production host: Escherichia coli (E. coli) / References: UniProt: O00255*PLUS

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Non-polymers , 6 types, 298 molecules

#2: Chemical ChemComp-EEV / 4-methyl-1-{[(2S)-5-oxomorpholin-2-yl]methyl}-5-[(4-{[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino}piperidin-1-yl)methyl]-1H-indole-2-carbonitrile


Mass: 597.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H30F3N7O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#5: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 288 / Source method: isolated from a natural source / Formula: H2O

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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 Å3/Da / Density % sol: 38.84 %
Crystal growTemperature: 283 K / Method: vapor diffusion, sitting drop
Details: 0.2 M ammonium acetate, 0.1 M HEPES and 25% w/v PEG 3,350. This solution was mixed 1:1 with 2.5mg/mL protein in 50mM Tris-HCl, 50mM NaCl, and 1mM TCEP. Prior to data collection, crystals ...Details: 0.2 M ammonium acetate, 0.1 M HEPES and 25% w/v PEG 3,350. This solution was mixed 1:1 with 2.5mg/mL protein in 50mM Tris-HCl, 50mM NaCl, and 1mM TCEP. Prior to data collection, crystals were transferred into a cryo-solution containing 20% PEG550 MME and flash-frozen in liquid nitrogen

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.0331 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Apr 9, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0331 Å / Relative weight: 1
ReflectionResolution: 1.82→50 Å / Num. obs: 42152 / % possible obs: 98.6 % / Redundancy: 6.5 % / Biso Wilson estimate: 20.5867950373 Å2 / Rmerge(I) obs: 0.083 / Net I/σ(I): 20.8
Reflection shellResolution: 1.82→1.86 Å / Rmerge(I) obs: 0.677 / Num. unique obs: 1972

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4X5Y

4x5y


Resolution: 1.82→40.27 Å / SU ML: 0.207 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 19.73
RfactorNum. reflection% reflection
Rfree0.2127 2121 5.03 %
Rwork0.1738 --
obs0.1758 42152 98.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 27.45 Å2
Refinement stepCycle: LAST / Resolution: 1.82→40.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3636 0 99 288 4023
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0152093179023859
X-RAY DIFFRACTIONf_angle_d1.344170779325245
X-RAY DIFFRACTIONf_chiral_restr0.0798429735114582
X-RAY DIFFRACTIONf_plane_restr0.0086758769038662
X-RAY DIFFRACTIONf_dihedral_angle_d5.297496933853110
LS refinement shellResolution: 1.8201→1.8624 Å
RfactorNum. reflection% reflection
Rfree0.33 132 -
Rwork0.24 2498 -
obs--95.1519536903 %
Refinement TLS params.Method: refined / Origin x: -11.5021844825 Å / Origin y: -11.8471316433 Å / Origin z: -13.2329353468 Å
111213212223313233
T0.0714384711044 Å20.0218069437226 Å20.0112704876882 Å2-0.144581207472 Å20.00197656331166 Å2--0.114787255311 Å2
L0.253506166127 °20.310806557624 °20.124367610992 °2-1.85468893823 °20.918162884935 °2--1.11835460487 °2
S0.00946871112067 Å °-0.044265551124 Å °0.0371351234533 Å °-0.0753747584924 Å °-0.0724779591173 Å °0.117393036764 Å °-0.0765744143407 Å °-0.0609016427272 Å °0.0296617771684 Å °
Refinement TLS groupSelection details: (chain A and resseq 2:588)

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