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- PDB-7m4t: Menin bound to M-1121 -

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Basic information

Entry
Database: PDB / ID: 7m4t
TitleMenin bound to M-1121
ComponentsMenin
KeywordsTRANSCRIPTION / 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 / R-SMAD binding / cleavage furrow / MLL1 complex / negative regulation of cell cycle / RHO GTPases activate IQGAPs / negative regulation of osteoblast differentiation / response to UV / four-way junction DNA binding / transcription initiation-coupled chromatin remodeling / transcription repressor complex / negative regulation of protein phosphorylation / Deactivation of the beta-catenin transactivating complex / response to gamma radiation / 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 / cytoplasm / cytosol
Similarity search - Function
praseodymium triacetate / Chem-YQV / Menin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.74 Å
AuthorsStuckey, J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)1-R01-CA208267 United States
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of M-1121 as an Orally Active Covalent Inhibitor of Menin-MLL Interaction Capable of Achieving Complete and Long-Lasting Tumor Regression.
Authors: Zhang, M. / Aguilar, A. / Xu, S. / Huang, L. / Chinnaswamy, K. / Sleger, T. / Wang, B. / Gross, S. / Nicolay, B.N. / Ronseaux, S. / Harvey, K. / Wang, Y. / McEachern, D. / Kirchhoff, P.D. / ...Authors: Zhang, M. / Aguilar, A. / Xu, S. / Huang, L. / Chinnaswamy, K. / Sleger, T. / Wang, B. / Gross, S. / Nicolay, B.N. / Ronseaux, S. / Harvey, K. / Wang, Y. / McEachern, D. / Kirchhoff, P.D. / Liu, Z. / Stuckey, J. / Tron, A.E. / Liu, T. / Wang, S.
History
DepositionMar 22, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 11, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)63,4467
Polymers61,0611
Non-polymers2,3856
Water181
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry, SEC
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)153.520, 153.520, 81.930
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number80
Space group name H-MI41
Components on special symmetry positions
IDModelComponents
11A-702-

7PR

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Components

#1: Protein Menin


Mass: 61061.234 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
#2: Chemical ChemComp-YQV / methyl {(1S,2R)-2-[(1S)-2-(azetidin-1-yl)-1-(3-fluorophenyl)-1-{1-[(3-methoxy-1-{4-[(1S,4S)-5-propanoyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonyl]phenyl}azetidin-3-yl)methyl]piperidin-4-yl}ethyl]cyclopentyl}carbamate


Mass: 795.018 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H59FN6O6S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-7PR / praseodymium triacetate


Mass: 318.040 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C6H9O6Pr
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.95 Å3/Da / Density % sol: 68.88 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 2.0 M NaCl, 90.9 M Bis-Tris pH 6.5, 0.182 M MgCl2, 10 mM Pr Acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.12714 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Apr 17, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.12714 Å / Relative weight: 1
ReflectionResolution: 2.74→50 Å / Num. obs: 24922 / % possible obs: 98.8 % / Redundancy: 5.4 % / Biso Wilson estimate: 60.56 Å2 / Rmerge(I) obs: 0.081 / Rpim(I) all: 0.039 / Rrim(I) all: 0.09 / Χ2: 0.884 / Net I/σ(I): 10.4 / Num. measured all: 134851
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.74-2.794.70.70411050.8060.3410.7840.77189.8
2.79-2.844.80.611970.8430.290.6680.77694.5
2.84-2.895.10.53212080.8680.2560.5920.78496.6
2.89-2.955.30.44812200.9260.2110.4960.79998.9
2.95-3.025.50.37212560.950.1750.4120.805100
3.02-3.095.70.34412480.9450.1610.3810.82100
3.09-3.165.70.2512750.9660.1170.2760.844100
3.16-3.255.70.19212310.9690.090.2130.932100
3.25-3.345.60.15812650.970.0750.1760.93199.8
3.34-3.455.30.12712550.9770.0620.1420.91399.9
3.45-3.584.70.09512670.9820.050.1080.95199.8
3.58-3.725.70.09212480.9840.0430.1011.13100
3.72-3.8960.07612630.9840.0350.0841.02299.9
3.89-4.095.90.06912650.9880.0320.0761.02699.9
4.09-4.355.80.05912500.9880.0280.0650.99299.8
4.35-4.685.60.05312690.9880.0250.0590.97799.8
4.68-5.165.60.04712590.990.0220.0520.96599.4
5.16-5.95.40.04512650.990.0220.050.81299.4
5.9-7.434.70.03612680.9920.0190.0410.63799.1
7.43-505.50.03413080.9950.0160.0370.65599.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
BUSTER2.10.3refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6WNH

6wnh


Resolution: 2.74→48.55 Å / Cor.coef. Fo:Fc: 0.894 / Cor.coef. Fo:Fc free: 0.873 / SU R Cruickshank DPI: 0.431 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.383 / SU Rfree Blow DPI: 0.242 / SU Rfree Cruickshank DPI: 0.252
RfactorNum. reflection% reflectionSelection details
Rfree0.215 1078 4.81 %RANDOM
Rwork0.202 ---
obs0.203 22432 89 %-
Displacement parametersBiso max: 116.05 Å2 / Biso mean: 43.35 Å2 / Biso min: 19.67 Å2
Baniso -1Baniso -2Baniso -3
1-0.4662 Å20 Å20 Å2
2--0.4662 Å20 Å2
3----0.9325 Å2
Refine analyzeLuzzati coordinate error obs: 0.4 Å
Refinement stepCycle: final / Resolution: 2.74→48.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3695 0 179 1 3875
Biso mean--41.4 23.28 -
Num. residues----481
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1793SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes686HARMONIC5
X-RAY DIFFRACTIONt_it4005HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion495SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4321SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4005HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg5544HARMONIC20.96
X-RAY DIFFRACTIONt_omega_torsion2.44
X-RAY DIFFRACTIONt_other_torsion2.64
LS refinement shellResolution: 2.74→2.77 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3072 33 7.35 %
Rwork0.2697 416 -
all0.2724 449 -
obs--56.8 %

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