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- PDB-6b41: Menin bound to M-525 -

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Basic information

Entry
Database: PDB / ID: 6b41
TitleMenin bound to M-525
ComponentsMenin
KeywordsPROTEIN BINDING/INHIBITOR / Covalent Inhibitor / MEN1 syndrome / leukemia / PROTEIN BINDING-INHIBITOR complex
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 / transcription initiation-coupled chromatin remodeling / negative regulation of protein phosphorylation / response to gamma radiation / Deactivation of the beta-catenin transactivating complex / 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 / cytosol / cytoplasm
Similarity search - Function
praseodymium triacetate / Chem-CJV / Menin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsStuckey, J.A.
CitationJournal: Angew. Chem. Int. Ed. Engl. / Year: 2018
Title: Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction.
Authors: Xu, S. / Aguilar, A. / Xu, T. / Zheng, K. / Huang, L. / Stuckey, J. / Chinnaswamy, K. / Bernard, D. / Fernandez-Salas, E. / Liu, L. / Wang, M. / McEachern, D. / Przybranowski, S. / Foster, C. / Wang, S.
History
DepositionSep 25, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 24, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 14, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.2Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_special_symmetry
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)63,0706
Polymers61,0611
Non-polymers2,0095
Water2,540141
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, mass spectrometry, Mass spectrometry data supports covalent bond between 525 and SG of C329
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)153.920, 153.920, 81.618
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-CJV / methyl {(1S,2R)-2-[(S)-cyano[1-({1-[4-({1-[4-(dimethylamino)butanoyl]azetidin-3-yl}sulfonyl)phenyl]azetidin-3-yl}methyl)piperidin-4-yl](3-fluorophenyl)methyl]cyclopentyl}carbamate


Mass: 736.939 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C39H53FN6O5S
#3: Chemical
ChemComp-7PR / praseodymium triacetate


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


Mass: 18.015 Da / Num. of mol.: 141 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 3.96 Å3/Da / Density % sol: 68.93 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 1.96 M NaCl, 89 mM Bis-Tris pH 6.8, 0.178 M MgCl2 and 10.7 mM Pr Acetate
PH range: 6.8

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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: Aug 2, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 2.61→50 Å / Num. obs: 29090 / % possible obs: 99.8 % / Redundancy: 12.1 % / Biso Wilson estimate: 51.84 Å2 / Rmerge(I) obs: 0.102 / Rpim(I) all: 0.031 / Rrim(I) all: 0.106 / Χ2: 0.921 / Net I/σ(I): 7.7 / Num. measured all: 350677
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.61-2.66110.66514140.910.2010.6960.70896.6
2.66-2.711.50.60814410.9270.1820.6350.74399.1
2.7-2.7611.90.55214300.9470.1640.5770.73999.9
2.76-2.8112.40.48914560.9540.1440.510.792100
2.81-2.8712.70.40214390.9640.1180.4190.811100
2.87-2.9412.80.35714330.9780.1040.3720.863100
2.94-3.0112.80.28814620.9890.0840.30.899100
3.01-3.0912.80.26414550.9870.0770.2750.922100
3.09-3.1912.70.20314340.9910.0590.2110.998100
3.19-3.2912.60.16914700.9910.050.1771.064100
3.29-3.4112.60.14914650.9940.0440.1551.094100
3.41-3.5412.40.12414440.9950.0370.1291.135100
3.54-3.712.20.10514420.9950.0320.111.145100
3.7-3.912.10.09514550.9960.0290.0991.119100
3.9-4.1411.80.08714590.9960.0260.0911.133100
4.14-4.4611.70.07814650.9960.0240.0821.061100
4.46-4.9111.50.07114490.9960.0220.0740.941100
4.91-5.6211.70.06814770.9970.0210.0710.858100
5.62-7.0811.50.06114790.9970.0190.0640.728100
7.08-5010.50.04915210.9980.0160.0520.581100

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
BUSTER2.10.3refinement
PDB_EXTRACT3.22data extraction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3U84

3u84


Resolution: 2.61→48.67 Å / Cor.coef. Fo:Fc: 0.865 / Cor.coef. Fo:Fc free: 0.818 / SU R Cruickshank DPI: 0.367 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.352 / SU Rfree Blow DPI: 0.263 / SU Rfree Cruickshank DPI: 0.269
RfactorNum. reflection% reflectionSelection details
Rfree0.252 1285 5 %RANDOM
Rwork0.209 ---
obs0.211 25715 88.2 %-
Displacement parametersBiso max: 216.28 Å2 / Biso mean: 40.26 Å2 / Biso min: 3 Å2
Baniso -1Baniso -2Baniso -3
1-0.8203 Å20 Å20 Å2
2--0.8203 Å20 Å2
3----1.6405 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: final / Resolution: 2.61→48.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3714 0 196 141 4051
Biso mean--79.76 36.67 -
Num. residues----481
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1348SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes84HARMONIC2
X-RAY DIFFRACTIONt_gen_planes606HARMONIC5
X-RAY DIFFRACTIONt_it3999HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion494SEMIHARMONIC5
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_contact4545SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3999HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg5514HARMONIC21.14
X-RAY DIFFRACTIONt_omega_torsion2.66
X-RAY DIFFRACTIONt_other_torsion19.52
LS refinement shellResolution: 2.61→2.72 Å / Rfactor Rfree error: 0 / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.2754 85 4.41 %
Rwork0.2242 1844 -
all0.2265 1929 -
obs--58.62 %

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