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- PDB-6by8: Menin in complex with MI-1482 -

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Basic information

Entry
Database: PDB / ID: 6by8
TitleMenin in complex with MI-1482
ComponentsMenin
KeywordsPROTEIN BINDING / inhibitor
Function / homology
Function and homology information


Y-form DNA binding / : / negative regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of JNK cascade / T-helper 2 cell differentiation / MLL1/2 complex / 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 cyclin-dependent protein serine/threonine kinase activity / negative regulation of JNK cascade / T-helper 2 cell differentiation / MLL1/2 complex / osteoblast development / histone methyltransferase complex / Formation of WDR5-containing histone-modifying complexes / positive regulation of transforming growth factor beta receptor signaling pathway / R-SMAD binding / cleavage furrow / MLL1 complex / negative regulation of cell cycle / negative regulation of osteoblast differentiation / RHO GTPases activate IQGAPs / four-way junction DNA binding / response to UV / transcription repressor complex / transcription initiation-coupled chromatin remodeling / negative regulation of protein phosphorylation / response to gamma radiation / Deactivation of the beta-catenin transactivating complex / phosphoprotein binding / Post-translational protein phosphorylation / 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 / negative regulation of cell population proliferation / endoplasmic reticulum lumen / 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: 1.9 Å
AuthorsBorkin, T. / 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 20, 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: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
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)56,15311
Polymers54,6001
Non-polymers1,55310
Water8,215456
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)48.991, 80.222, 124.722
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: 54600.246 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

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Non-polymers , 6 types, 466 molecules

#2: Chemical ChemComp-FNV / 4-methyl-1-{[(2R)-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


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


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


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


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


Mass: 18.015 Da / Num. of mol.: 456 / 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: 2.11 Å3/Da / Density % sol: 41.83 %
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: Jun 22, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0331 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 54917 / % possible obs: 100 % / Redundancy: 3.2 % / Biso Wilson estimate: 14.6947939233 Å2 / Rmerge(I) obs: 0.082 / Net I/σ(I): 12.48
Reflection shellResolution: 1.9→1.93 Å / Rmerge(I) obs: 0.508 / Num. unique all: 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: 1.9→38.52 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 16.31
RfactorNum. reflection% reflection
Rfree0.188 2024 5.12 %
Rwork0.1505 --
obs0.1524 39551 99.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 18.74 Å2
Refinement stepCycle: LAST / Resolution: 1.9→38.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3657 0 98 456 4211
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007891754340413908
X-RAY DIFFRACTIONf_angle_d0.8815435501295314
X-RAY DIFFRACTIONf_chiral_restr0.0504545823666592
X-RAY DIFFRACTIONf_plane_restr0.00525020807061670
X-RAY DIFFRACTIONf_dihedral_angle_d15.76441311222355
LS refinement shellResolution: 1.9→1.9475 Å
RfactorNum. reflection% reflection
Rfree0.197 147 -
Rwork0.14 2641 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 13.0523688643 Å / Origin y: 11.6777166463 Å / Origin z: 13.9912356281 Å
111213212223313233
T0.0381606689031 Å2-0.0110161653713 Å2-0.00261823315105 Å2-0.0730391640593 Å20.0116843037937 Å2--0.0560293445723 Å2
L0.268338590747 °2-0.225629899856 °2-0.104717686221 °2-1.03323936873 °20.49427983047 °2--0.728236995177 °2
S-0.000114567938061 Å °0.0523701064189 Å °0.00221734531145 Å °-0.000185408272129 Å °-0.0280418089653 Å °0.0148161050071 Å °0.0288054345992 Å °-0.00774985969135 Å °0.0160344943276 Å °
Refinement TLS groupSelection details: (chain A and resseq 2:588)

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