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- PDB-6o5i: Menin in complex with MI-3454 -

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Basic information

Entry
Database: PDB / ID: 6o5i
TitleMenin in complex with MI-3454
ComponentsMenin
KeywordsPROTEIN BINDING / Menin-inhibitor complex
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: 1.24025624626 Å
AuthorsLinhares, B.M. / Klossowski, S. / Cierpicki, T. / Grembecka, J.
Funding support United States, 2items
OrganizationGrant numberCountry
Department of Energy (DOE, United States) United States
National Institutes of Health/National Library of Medicine (NIH/NLM)1R01CA160467 NIH R01 United States
CitationJournal: J.Clin.Invest. / Year: 2020
Title: Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia.
Authors: Klossowski, S. / Miao, H. / Kempinska, K. / Wu, T. / Purohit, T. / Kim, E. / Linhares, B.M. / Chen, D. / Jih, G. / Perkey, E. / Huang, H. / He, M. / Wen, B. / Wang, Y. / Yu, K. / Lee, S.C. / ...Authors: Klossowski, S. / Miao, H. / Kempinska, K. / Wu, T. / Purohit, T. / Kim, E. / Linhares, B.M. / Chen, D. / Jih, G. / Perkey, E. / Huang, H. / He, M. / Wen, B. / Wang, Y. / Yu, K. / Lee, S.C. / Danet-Desnoyers, G. / Trotman, W. / Kandarpa, M. / Cotton, A. / Abdel-Wahab, O. / Lei, H. / Dou, Y. / Guzman, M. / Peterson, L. / Gruber, T. / Choi, S. / Sun, D. / Ren, P. / Li, L.S. / Liu, Y. / Burrows, F. / Maillard, I. / Cierpicki, T. / Grembecka, J.
History
DepositionMar 3, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 8, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2020Group: Database references / Category: citation / citation_author / Item: _citation.year / _citation_author.name
Revision 1.2Feb 19, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 11, 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)56,03210
Polymers54,6001
Non-polymers1,4329
Water15,691871
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)49.092, 79.843, 124.261
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 , 5 types, 880 molecules

#2: Chemical ChemComp-LMY / ~{N}-[3-[[2-cyano-4-methyl-5-[[4-[[2-(methylamino)-6-[2,2,2-tris(fluoranyl)ethyl]thieno[2,3-d]pyrimidin-4-yl]amino]piperidin-1-yl]methyl]indol-1-yl]methyl]-1-bicyclo[1.1.1]pentanyl]methanamide


Mass: 636.734 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H35F3N8OS / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 871 / 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: 2.32 Å3/Da / Density % sol: 47.05 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.2 M lithium sulfate, 0.1 M HEPES, pH 7.5, 25% (w/v) PEG-3,350.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.987 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Oct 18, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 1.24→50 Å / Num. obs: 138482 / % possible obs: 99.8 % / Redundancy: 7.2 % / Biso Wilson estimate: 13.580403913 Å2 / Rmerge(I) obs: 0.079 / Net I/σ(I): 18.03
Reflection shellResolution: 1.24→1.28 Å / Rmerge(I) obs: 0.697 / Num. unique obs: 13583

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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: 1.24025624626→28.7440371989 Å / SU ML: 0.107792008628 / Cross valid method: FREE R-VALUE / σ(F): 1.3629061364 / Phase error: 13.9359843005
RfactorNum. reflection% reflection
Rfree0.163773291427 6900 4.98266897747 %
Rwork0.126364815608 --
obs0.128174324274 138480 99.8313075825 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 21.5809745805 Å2
Refinement stepCycle: LAST / Resolution: 1.24025624626→28.7440371989 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3617 0 89 871 4577
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01303671615553898
X-RAY DIFFRACTIONf_angle_d1.315121218065314
X-RAY DIFFRACTIONf_chiral_restr0.0913754161273585
X-RAY DIFFRACTIONf_plane_restr0.0082418437075673
X-RAY DIFFRACTIONf_dihedral_angle_d17.90585573281399
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.2403-1.25430.2524836742322270.2214457917014168X-RAY DIFFRACTION95.8560523446
1.2543-1.26910.1926125507122220.1968217981794359X-RAY DIFFRACTION100
1.2691-1.28460.2264887901792220.1839887905834385X-RAY DIFFRACTION100
1.2846-1.30080.2185827013592300.1713899574271X-RAY DIFFRACTION99.9777876499
1.3008-1.3180.2068628793762520.1598111655224332X-RAY DIFFRACTION100
1.318-1.3360.1877138142482350.1507389793874358X-RAY DIFFRACTION100
1.336-1.35510.1923217935092330.140385823054346X-RAY DIFFRACTION100
1.3551-1.37530.1717675590942010.1364263131844383X-RAY DIFFRACTION100
1.3753-1.39680.1894979421012350.1329601291574356X-RAY DIFFRACTION100
1.3968-1.41970.172746413132290.1279163719994349X-RAY DIFFRACTION99.9781611706
1.4197-1.44420.1728006193032440.1248463044094356X-RAY DIFFRACTION100
1.4442-1.47050.1624346650771940.1224251118174346X-RAY DIFFRACTION100
1.4705-1.49870.161736893922360.1124874330664383X-RAY DIFFRACTION100
1.4987-1.52930.1558564693552170.1026949532334365X-RAY DIFFRACTION100
1.5293-1.56260.1349503439632400.101919256544346X-RAY DIFFRACTION100
1.5626-1.59890.1268170725742000.09837290654644399X-RAY DIFFRACTION100
1.5989-1.63890.1382515498922590.09308195822314371X-RAY DIFFRACTION100
1.6389-1.68320.1439841471012450.09336678746034338X-RAY DIFFRACTION100
1.6832-1.73270.1351973522022460.09404848574494364X-RAY DIFFRACTION100
1.7327-1.78870.1400507914282200.1001318032494375X-RAY DIFFRACTION100
1.7887-1.85260.1322446877112270.1027848759944403X-RAY DIFFRACTION100
1.8526-1.92670.1627739721542080.1078914364724427X-RAY DIFFRACTION100
1.9267-2.01440.1446565535332330.1094306179874391X-RAY DIFFRACTION100
2.0144-2.12060.1563438724812450.1105708863874420X-RAY DIFFRACTION100
2.1206-2.25340.1403282582262540.111224399954393X-RAY DIFFRACTION100
2.2534-2.42730.1533374386742390.1210627110424439X-RAY DIFFRACTION100
2.4273-2.67140.1620192942182220.1306570121374449X-RAY DIFFRACTION100
2.6714-3.05760.1792373230952200.1392441284064499X-RAY DIFFRACTION99.957636094
3.0576-3.85080.181057773722240.1247225405274527X-RAY DIFFRACTION100
3.8508-28.75170.1736777552192410.1556279036024682X-RAY DIFFRACTION99.1940358654

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