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- PDB-8va6: Menin in complex with Ziftomenib (KO-539) -

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Basic information

Entry
Database: PDB / ID: 8va6
TitleMenin in complex with Ziftomenib (KO-539)
ComponentsMenin
KeywordsPROTEIN BINDING
Function / homology
Function and homology information


Y-form DNA binding / negative regulation of cyclin-dependent protein serine/threonine kinase activity / MLL1/2 complex / negative regulation of JNK cascade / osteoblast development / T-helper 2 cell differentiation / histone methyltransferase complex / Formation of WDR5-containing histone-modifying complexes / positive regulation of transforming growth factor beta receptor signaling pathway / R-SMAD binding ...Y-form DNA binding / negative regulation of cyclin-dependent protein serine/threonine kinase activity / MLL1/2 complex / negative regulation of JNK cascade / osteoblast development / T-helper 2 cell differentiation / 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 protein phosphorylation / negative regulation of osteoblast differentiation / RHO GTPases activate IQGAPs / response to UV / four-way junction DNA binding / transcription repressor complex / transcription initiation-coupled chromatin remodeling / response to gamma radiation / negative regulation of DNA-binding transcription factor activity / phosphoprotein binding / Post-translational protein phosphorylation / Deactivation of the beta-catenin transactivating complex / Formation of the beta-catenin:TCF transactivating complex / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / nuclear matrix / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / MAPK cascade / double-stranded DNA binding / protein-macromolecule adaptor activity / 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 / regulation of transcription by RNA polymerase II / chromatin / 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
: / DI(HYDROXYETHYL)ETHER / Menin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.57 Å
AuthorsClegg, B.D. / Linhares, B.M. / Cierpicki, T. / Grembecka, J.
Funding support United States, 1items
OrganizationGrant numberCountry
Leukemia & Lymphoma Society6485-16 United States
CitationJournal: Lancet Oncol / Year: 2024
Title: Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial.
Authors: Wang, E.S. / Issa, G.C. / Erba, H.P. / Altman, J.K. / Montesinos, P. / DeBotton, S. / Walter, R.B. / Pettit, K. / Savona, M.R. / Shah, M.V. / Kremyanskaya, M. / Baer, M.R. / Foran, J.M. / ...Authors: Wang, E.S. / Issa, G.C. / Erba, H.P. / Altman, J.K. / Montesinos, P. / DeBotton, S. / Walter, R.B. / Pettit, K. / Savona, M.R. / Shah, M.V. / Kremyanskaya, M. / Baer, M.R. / Foran, J.M. / Schiller, G. / Ades, L. / Heiblig, M. / Berthon, C. / Peterlin, P. / Rodriguez-Arboli, E. / Salamero, O. / Patnaik, M.M. / Papayannidis, C. / Grembecka, J. / Cierpicki, T. / Clegg, B. / Ray, J. / Linhares, B.M. / Nie, K. / Mitra, A. / Ahsan, J.M. / Tabachri, M. / Soifer, H.S. / Corum, D. / Leoni, M. / Dale, S. / Fathi, A.T.
History
DepositionDec 11, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 20, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 4, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _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

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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)56,42512
Polymers54,6001
Non-polymers1,82511
Water6,666370
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)48.395, 80.181, 124.924
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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 , 7 types, 381 molecules

#2: Chemical ChemComp-K5O / Ziftomenib


Mass: 717.871 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H42F3N9O2S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#7: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 18.015 Da / Num. of mol.: 370 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.22 Å3/Da / Density % sol: 44.61 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
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-G / Wavelength: 0.97857 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jun 7, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 1.57→50 Å / Num. obs: 68768 / % possible obs: 100 % / Redundancy: 6.9 % / Rmerge(I) obs: 0.072 / Net I/σ(I): 33.4
Reflection shellResolution: 1.57→1.6 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.772 / Mean I/σ(I) obs: 2.13 / Num. unique obs: 0 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
HKL-2000722data reduction
HKL-2000722data scaling
MOLREP11.0 /22.07.2010/phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.57→41.467 Å / Cor.coef. Fo:Fc: 0.974 / Cor.coef. Fo:Fc free: 0.963 / SU B: 1.577 / SU ML: 0.055 / Cross valid method: THROUGHOUT / ESU R: 0.075 / ESU R Free: 0.079
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1933 3434 4.999 %
Rwork0.1581 65261 -
all0.16 --
obs-68695 99.952 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 23.252 Å2
Baniso -1Baniso -2Baniso -3
1-1.513 Å2-0 Å20 Å2
2--0.053 Å2-0 Å2
3----1.566 Å2
Refinement stepCycle: LAST / Resolution: 1.57→41.467 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3670 0 116 370 4156
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0123963
X-RAY DIFFRACTIONr_bond_other_d0.0010.0163746
X-RAY DIFFRACTIONr_angle_refined_deg1.8251.835382
X-RAY DIFFRACTIONr_angle_other_deg0.6481.7438602
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.135485
X-RAY DIFFRACTIONr_dihedral_angle_2_deg9.052630
X-RAY DIFFRACTIONr_dihedral_angle_other_2_deg4.733202
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.18310641
X-RAY DIFFRACTIONr_dihedral_angle_6_deg15.07710176
X-RAY DIFFRACTIONr_chiral_restr0.1010.2595
X-RAY DIFFRACTIONr_chiral_restr_other0.0040.21
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.024682
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02928
X-RAY DIFFRACTIONr_nbd_refined0.2220.2805
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1830.23293
X-RAY DIFFRACTIONr_nbtor_refined0.1830.21943
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0740.21970
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1350.2227
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2390.212
X-RAY DIFFRACTIONr_nbd_other0.1860.273
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2790.216
X-RAY DIFFRACTIONr_mcbond_it2.4672.2631918
X-RAY DIFFRACTIONr_mcbond_other2.4672.2631918
X-RAY DIFFRACTIONr_mcangle_it3.6624.0552411
X-RAY DIFFRACTIONr_mcangle_other3.6634.0572412
X-RAY DIFFRACTIONr_scbond_it3.7292.6252045
X-RAY DIFFRACTIONr_scbond_other3.7282.6262046
X-RAY DIFFRACTIONr_scangle_it5.5364.6162971
X-RAY DIFFRACTIONr_scangle_other5.5354.6172972
X-RAY DIFFRACTIONr_lrange_it6.97824.7164546
X-RAY DIFFRACTIONr_lrange_other6.97724.724547
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.57-1.6110.242400.2447800.2450370.9570.95599.66250.215
1.611-1.6550.2382600.21645920.21748520.9590.9651000.187
1.655-1.7030.2422460.19644940.19847400.9580.9721000.168
1.703-1.7550.232440.19443770.19546210.9650.9731000.163
1.755-1.8120.2172280.17242560.17444840.9670.981000.143
1.812-1.8760.1942090.16441410.16543500.9750.9821000.138
1.876-1.9470.2112200.15839820.16142020.9720.9831000.133
1.947-2.0260.1942120.14938410.15140530.9760.9861000.13
2.026-2.1160.2111840.14836930.15138770.9720.9861000.131
2.116-2.2190.1811700.14435360.14637060.9790.9871000.131
2.219-2.3380.1841890.1433490.14335380.9770.9881000.13
2.338-2.480.2011710.13931910.14233620.9770.9881000.13
2.48-2.650.1741430.14430390.14531820.9810.9871000.138
2.65-2.8620.191530.14628200.14829730.9770.9871000.144
2.862-3.1330.2111290.16525950.16727240.9730.9841000.168
3.133-3.50.1791300.16123590.16224890.980.9851000.17
3.5-4.0370.1511040.13821230.13822270.9890.9891000.151
4.037-4.9330.176970.1417990.14118960.9840.9891000.161
4.933-6.9270.207580.19314440.19415020.9790.9831000.219
6.927-41.4670.216470.1828500.1849090.9770.98198.67990.226

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