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- PDB-8va5: Menin mutant - T349M in complex with Ziftomenib (KO-539) -

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Basic information

Entry
Database: PDB / ID: 8va5
TitleMenin mutant - T349M 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: 1.3 Å
AuthorsClegg, B.D. / Cierpicki, T. / Grembecka, J.
Funding support United States, 1items
OrganizationGrant numberCountry
Leukemia & Lymphoma Society6649-23 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)55,9738
Polymers54,6301
Non-polymers1,3437
Water11,422634
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1150 Å2
ΔGint9 kcal/mol
Surface area21010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.057, 80.034, 124.823
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: 54630.340 Da / Num. of mol.: 1 / Mutation: T349M
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, 641 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-PG4 / TETRAETHYLENE GLYCOL


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


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 634 / 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: 2.24 Å3/Da / Density % sol: 45.16 %
Crystal growTemperature: 285 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-G / Wavelength: 0.97857 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Apr 8, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 1.3→50 Å / Num. obs: 120002 / % possible obs: 98.9 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.133 / Net I/σ(I): 24.51
Reflection shellResolution: 1.3→1.32 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.981 / Mean I/σ(I) obs: 2.03 / Num. unique obs: 0 / % possible all: 96.1

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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: 1.3→26.344 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.966 / SU B: 0.823 / SU ML: 0.034 / Cross valid method: THROUGHOUT / ESU R: 0.047 / ESU R Free: 0.05
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1858 6193 5.165 %
Rwork0.1607 113718 -
all0.162 --
obs-119911 98.737 %
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: 13.487 Å2
Baniso -1Baniso -2Baniso -3
1-0.728 Å2-0 Å20 Å2
2--0.372 Å2-0 Å2
3----1.1 Å2
Refinement stepCycle: LAST / Resolution: 1.3→26.344 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3667 0 88 634 4389
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0124136
X-RAY DIFFRACTIONr_bond_other_d0.0010.0163912
X-RAY DIFFRACTIONr_angle_refined_deg2.0051.8375639
X-RAY DIFFRACTIONr_angle_other_deg0.6821.759004
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8585525
X-RAY DIFFRACTIONr_dihedral_angle_2_deg13.4125.90933
X-RAY DIFFRACTIONr_dihedral_angle_other_2_deg3.923202
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.74810691
X-RAY DIFFRACTIONr_dihedral_angle_6_deg15.41410184
X-RAY DIFFRACTIONr_chiral_restr0.1050.2612
X-RAY DIFFRACTIONr_chiral_restr_other0.0020.21
X-RAY DIFFRACTIONr_gen_planes_refined0.010.025024
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02990
X-RAY DIFFRACTIONr_nbd_refined0.2380.2863
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1820.23437
X-RAY DIFFRACTIONr_nbtor_refined0.1860.22014
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0750.21943
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1530.2371
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0770.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2020.222
X-RAY DIFFRACTIONr_nbd_other0.2070.2102
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1690.244
X-RAY DIFFRACTIONr_mcbond_it1.5171.2782018
X-RAY DIFFRACTIONr_mcbond_other1.5171.2782018
X-RAY DIFFRACTIONr_mcangle_it2.2722.2962570
X-RAY DIFFRACTIONr_mcangle_other2.2722.2972571
X-RAY DIFFRACTIONr_scbond_it2.5951.5152118
X-RAY DIFFRACTIONr_scbond_other2.5941.5162119
X-RAY DIFFRACTIONr_scangle_it3.932.6513069
X-RAY DIFFRACTIONr_scangle_other3.9292.6523070
X-RAY DIFFRACTIONr_lrange_it5.4917.6274975
X-RAY DIFFRACTIONr_lrange_other5.48917.6284976
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
1.3-1.3340.2764340.25979600.2688630.950.95494.70830.247
1.334-1.370.2554450.23879300.23986300.9530.96197.04520.22
1.37-1.410.2493880.21978090.22184130.9610.96797.43250.2
1.41-1.4530.234040.20375820.20581550.9670.97297.92770.182
1.453-1.50.214370.18673470.18879280.9690.97698.18370.164
1.5-1.5530.1993740.17271890.17376690.9730.9898.61780.151
1.553-1.6110.1923730.16369980.16574320.9770.98299.17920.143
1.611-1.6770.1663750.15567550.15671700.9820.98499.44210.136
1.677-1.7510.1854170.15464110.15668530.9780.98599.63520.136
1.751-1.8360.1733260.14762410.14965780.980.98699.83280.133
1.836-1.9350.1893160.15159080.15362280.9780.98699.93580.138
1.935-2.0510.1762870.14956990.1559910.9820.98799.91650.141
2.051-2.1920.1672990.14652470.14755480.9830.98799.9640.142
2.192-2.3660.1662460.13149980.13352440.9840.9891000.13
2.366-2.590.1622680.13745800.13848480.9830.9881000.138
2.59-2.8920.1811970.1541850.15143820.980.9861000.155
2.892-3.3330.2052110.15336870.15638980.9760.9861000.163
3.333-4.0660.1491640.1431790.14133430.9870.9881000.156
4.066-5.6830.1681330.15925060.15926390.990.9881000.182
5.683-26.3440.226990.2215080.22116140.9730.97999.56630.258

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