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- PDB-6e1a: Menin bound to M-89 -

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Basic information

Entry
Database: PDB / ID: 6e1a
TitleMenin bound to M-89
ComponentsMenin
KeywordsPROTEIN BINDING / inhibitor / transcription
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 / T-helper 2 cell differentiation / MLL1/2 complex / 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 / T-helper 2 cell differentiation / MLL1/2 complex / 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 / negative regulation of osteoblast differentiation / RHO GTPases activate IQGAPs / four-way junction DNA binding / response to UV / transcription repressor complex / negative regulation of protein phosphorylation / transcription initiation-coupled chromatin remodeling / response to gamma radiation / Deactivation of the beta-catenin transactivating complex / Post-translational protein phosphorylation / 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 / 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 / cytosol / cytoplasm
Similarity search - Function
praseodymium triacetate / Chem-HL7 / Menin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.1 Å
AuthorsStuckey, J.A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)1-R01-CA-208267-01-A1 United States
CitationJournal: J.Med.Chem. / Year: 2019
Title: Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein-Protein Interaction.
Authors: Aguilar, A. / Zheng, K. / Xu, T. / Xu, S. / Huang, L. / Fernandez-Salas, E. / Liu, L. / Bernard, D. / Harvey, K.P. / Foster, C. / McEachern, D. / Stuckey, J. / Chinnaswamy, K. / Delproposto, ...Authors: Aguilar, A. / Zheng, K. / Xu, T. / Xu, S. / Huang, L. / Fernandez-Salas, E. / Liu, L. / Bernard, D. / Harvey, K.P. / Foster, C. / McEachern, D. / Stuckey, J. / Chinnaswamy, K. / Delproposto, J. / Kampf, J.W. / Wang, S.
History
DepositionJul 9, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 24, 2019Group: Data collection / 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 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
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

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Assembly

Deposited unit
A: Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,3097
Polymers61,0611
Non-polymers2,2486
Water46826
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry, Gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)154.210, 154.210, 82.620
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number80
Space group name H-MI41

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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-HL7 / (1S,2R)-2-[(4S)-2-methyl-4-{1-[(1-{4-[(pyridin-4-yl)sulfonyl]phenyl}azetidin-3-yl)methyl]piperidin-4-yl}-1,2,3,4-tetrahydroisoquinolin-4-yl]cyclopentyl methylcarbamate


Mass: 657.865 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H47N5O4S
#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.: 26 / 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: 4.02 Å3/Da / Density % sol: 69.42 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 2.0 M sodium chloride, 90.9 M Bis-Tris pH 6.5, 0.182 M Magnesium chloride, 9 mM Praseodymium Acetate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.9786 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Nov 11, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 3.1→50 Å / Num. obs: 17860 / % possible obs: 100 % / Redundancy: 14.1 % / Biso Wilson estimate: 72.38 Å2 / Rmerge(I) obs: 0.072 / Rpim(I) all: 0.02 / Rrim(I) all: 0.074 / Χ2: 0.969 / Net I/σ(I): 8.4 / Num. measured all: 251403
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2
3.1-3.1515.30.4179020.9880.110.4310.84
3.15-3.2115.30.3418580.9920.090.3530.863
3.21-3.2715.30.2778840.9940.0730.2860.871
3.27-3.3415.20.2419180.9960.0640.2490.888
3.34-3.4115.20.2198550.9960.0580.2270.897
3.41-3.4915.10.1798910.9970.0480.1850.956
3.49-3.58150.1428870.9980.0380.1470.965
3.58-3.6814.90.1118860.9980.030.1150.956
3.68-3.7814.80.1118990.9980.030.1151.049
3.78-3.9114.70.0969220.9980.0260.11.092
3.91-4.0414.60.0828520.9980.0230.0861.135
4.04-4.2114.40.0728980.9990.020.0751.121
4.21-4.414.30.0668740.9980.0190.0691.081
4.4-4.63140.0598930.9990.0170.0611.113
4.63-4.9213.80.0559030.9990.0160.0571.067
4.92-5.313.50.0498940.9990.0140.0510.986
5.3-5.8313.10.0489180.9990.0140.050.898
5.83-6.6712.50.0428770.9990.0130.0440.86
6.67-8.411.40.0349160.9990.0110.0360.782
8.4-509.40.0329330.9980.0110.0340.907

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
BUSTER2.10.3refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3U84

3u84


Resolution: 3.1→48.77 Å / Cor.coef. Fo:Fc: 0.926 / Cor.coef. Fo:Fc free: 0.888 / SU R Cruickshank DPI: 1.148 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.896 / SU Rfree Blow DPI: 0.348 / SU Rfree Cruickshank DPI: 0.361
RfactorNum. reflection% reflectionSelection details
Rfree0.235 856 5.22 %RANDOM
Rwork0.188 ---
obs0.19 16414 91.6 %-
Displacement parametersBiso max: 197.44 Å2 / Biso mean: 61.56 Å2 / Biso min: 9.43 Å2
Baniso -1Baniso -2Baniso -3
1-2.359 Å20 Å20 Å2
2--2.359 Å20 Å2
3----4.7179 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: final / Resolution: 3.1→48.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3698 0 112 26 3836
Biso mean--102.17 44.81 -
Num. residues----481
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1767SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes81HARMONIC2
X-RAY DIFFRACTIONt_gen_planes604HARMONIC5
X-RAY DIFFRACTIONt_it3900HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion493SEMIHARMONIC5
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_contact4436SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3900HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg5310HARMONIC20.98
X-RAY DIFFRACTIONt_omega_torsion2.31
X-RAY DIFFRACTIONt_other_torsion2.88
LS refinement shellResolution: 3.09→3.3 Å / Rfactor Rfree error: 0 / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2744 110 4.8 %
Rwork0.2244 2183 -
all0.2271 2293 -
obs--71.04 %

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