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- PDB-6wnh: Menin bound to inhibitor M-808 -

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Basic information

Entry
Database: PDB / ID: 6wnh
TitleMenin bound to inhibitor M-808
ComponentsMenin
KeywordsTRANSCRIPTION / Inhibitor / PROTEIN BINDING
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 / 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 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
Chem-7MM / praseodymium triacetate / Menin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsStuckey, J.A.
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: 2020
Title: Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin-MLL Interaction with StrongIn VivoAntitumor Activity.
Authors: Xu, S. / Aguilar, A. / Huang, L. / Xu, T. / Zheng, K. / McEachern, D. / Przybranowski, S. / Foster, C. / Zawacki, K. / Liu, Z. / Chinnaswamy, K. / Stuckey, J. / Wang, S.
History
DepositionApr 22, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 13, 2020Provider: repository / Type: Initial release
Revision 1.1May 27, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 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)63,4737
Polymers61,0611
Non-polymers2,4116
Water4,540252
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Mass Spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)153.549, 153.549, 81.283
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-7MM / methyl [(1S,2R)-2-{(1S)-2-(azetidin-1-yl)-1-(3-fluorophenyl)-1-[1-({1-[4-({1-[4-(piperidin-1-yl)butanoyl]azetidin-3-yl}sulfonyl)phenyl]azetidin-3-yl}methyl)piperidin-4-yl]ethyl}cyclopentyl]carbamate


Mass: 821.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C45H65FN6O5S / 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.: 252 / 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: 3.92 Å3/Da / Density % sol: 68.65 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.8
Details: 1.96 M NaCl, 89 mM Bis-Tris pH 6.8, 0.178 M MgCl2 and 10.7 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-F / Wavelength: 0.9787 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 31, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 55230 / % possible obs: 99.9 % / Redundancy: 6.9 % / Rmerge(I) obs: 0.102 / Rpim(I) all: 0.042 / Rrim(I) all: 0.11 / Net I/σ(I): 5.9
Reflection shellResolution: 2.1→2.14 Å / Redundancy: 4.9 % / Rmerge(I) obs: 2.55 / Num. unique obs: 2722 / CC1/2: 0.241 / Rpim(I) all: 1.274 / Rrim(I) all: 2.864 / Χ2: 0.591 / % possible all: 99

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3U84

3u84


Resolution: 2.1→48.56 Å / Cor.coef. Fo:Fc: 0.918 / Cor.coef. Fo:Fc free: 0.89 / SU R Cruickshank DPI: 0.211 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.209 / SU Rfree Blow DPI: 0.183 / SU Rfree Cruickshank DPI: 0.184
RfactorNum. reflection% reflectionSelection details
Rfree0.228 1722 4.76 %RANDOM
Rwork0.191 ---
obs0.193 36178 65.8 %-
Displacement parametersBiso max: 139.01 Å2 / Biso mean: 36 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-0.3913 Å20 Å20 Å2
2--0.3913 Å20 Å2
3----0.7826 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: final / Resolution: 2.1→48.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3701 0 232 252 4185
Biso mean--48.35 35.27 -
Num. residues----481
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1805SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes686HARMONIC5
X-RAY DIFFRACTIONt_it4024HARMONIC20
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_contact4639SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4024HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg5578HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion2.86
X-RAY DIFFRACTIONt_other_torsion2.71
LS refinement shellResolution: 2.1→2.15 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2453 30 4.14 %
Rwork0.2186 694 -
all0.2197 724 -
obs--21.33 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.97910.63790.33491.3998-0.08871.07880.02150.0606-0.2131-0.0006-0.1037-0.0349-0.0315-0.03630.0822-0.10730.02730.0495-0.02830.02060.0399-40.64453.5985-28.3166
21.90890.41810.35811.28380.24490.78180.0605-0.141-0.2210.1575-0.0396-0.0127-0.0484-0.1516-0.0209-0.08490.00130.0569-0.09220.0942-0.031-25.887610.9633-16.2033
30.9099-0.1110.2861.21280.90771.0536-0.00860.1653-0.0699-0.03970.2138-0.3495-0.02890.1761-0.2052-0.1056-0.04450.0944-0.1216-0.01160.13964.988118.046-24.51
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|2 - 81}A2 - 81
2X-RAY DIFFRACTION2{A|82 - 333}A82 - 333
3X-RAY DIFFRACTION3{A|334 - 581}A334 - 581

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