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- PDB-5dda: Menin in complex with MI-333 -

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Basic information

Entry
Database: PDB / ID: 5dda
TitleMenin in complex with MI-333
ComponentsMenin
KeywordsPROTEIN BINDING/INHIBITOR / PROTEIN BINDING-INHIBITOR complex
Function / homology
Function and homology information


negative regulation of cyclin-dependent protein serine/threonine kinase activity / Y-form DNA binding / MLL1/2 complex / osteoblast development / negative regulation of JNK cascade / T-helper 2 cell differentiation / Formation of WDR5-containing histone-modifying complexes / positive regulation of transforming growth factor beta receptor signaling pathway / negative regulation of protein phosphorylation / histone methyltransferase complex ...negative regulation of cyclin-dependent protein serine/threonine kinase activity / Y-form DNA binding / MLL1/2 complex / osteoblast development / negative regulation of JNK cascade / T-helper 2 cell differentiation / Formation of WDR5-containing histone-modifying complexes / positive regulation of transforming growth factor beta receptor signaling pathway / negative regulation of protein phosphorylation / histone methyltransferase complex / negative regulation of cell cycle / R-SMAD binding / cleavage furrow / MLL1 complex / negative regulation of osteoblast differentiation / RHO GTPases activate IQGAPs / negative regulation of DNA-binding transcription factor activity / response to UV / four-way junction DNA binding / transcription repressor complex / transcription initiation-coupled chromatin remodeling / response to gamma radiation / Post-translational protein phosphorylation / Deactivation of the beta-catenin transactivating complex / phosphoprotein binding / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Formation of the beta-catenin:TCF transactivating complex / 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 / cytoplasm / cytosol
Similarity search - Function
Chem-59M / TRIETHYLENE GLYCOL / Menin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 Å
AuthorsPollock, J. / Dmitry, B. / Cierpicki, T. / Grembecka, J.
Funding support United States, 8items
OrganizationGrant numberCountry
American Cancer SocietyRSG-11-082-01-DMC United States
American Cancer SocietyRSG-13-130-01-CDD United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA181185 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA160467 United States
Leukemia & Lymphoma Society1215-14 United States
Leukemia & Lymphoma Society6116-12 United States
Department of Energy (DOE, United States)DE-AC02-06CH11357 United States
LS-CAT 635 Sector 21085P1000817 United States
CitationJournal: J.Med.Chem. / Year: 2015
Title: Rational Design of Orthogonal Multipolar Interactions with Fluorine in Protein-Ligand Complexes.
Authors: Pollock, J. / Borkin, D. / Lund, G. / Purohit, T. / Dyguda-Kazimierowicz, E. / Grembecka, J. / Cierpicki, T.
History
DepositionAug 24, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 9, 2015Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2015Group: Database references
Revision 1.2Sep 27, 2017Group: Author supporting evidence / Database references / Derived calculations
Category: citation / pdbx_audit_support / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Sep 27, 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)56,14414
Polymers54,5701
Non-polymers1,57413
Water4,792266
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.133, 79.998, 124.668
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 54570.223 Da / Num. of mol.: 1 / Fragment: UNP residues 1-459, 537-593 / Mutation: A541T
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, 279 molecules

#2: Chemical ChemComp-59M / 4-{4-[5-(fluoromethyl)-1,3,4-thiadiazol-2-yl]piperazin-1-yl}-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine


Mass: 418.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H14F4N6S2
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H14O4
#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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 266 / 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: 2.2 Å3/Da / Density % sol: 44.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.2 M ammonium acetate, 0.1 M HEPES and 25% w/v PEG 3,350. This solution was mixed 1:1 with 2.5mg/mL protein in 50mM Tris-HCl, 50mM NaCl, and 1mM TCEP. Prior to data collection, crystals ...Details: 0.2 M ammonium acetate, 0.1 M HEPES and 25% w/v PEG 3,350. This solution was mixed 1:1 with 2.5mg/mL protein in 50mM Tris-HCl, 50mM NaCl, and 1mM TCEP. Prior to data collection, crystals were transferred into a cryo-solution containing 20% PEG550 MME and flash-frozen in liquid nitrogen

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Aug 11, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.83→50 Å / Num. obs: 43420 / % possible obs: 100 % / Redundancy: 6.9 % / Rmerge(I) obs: 0.09 / Χ2: 1.266 / Net I/av σ(I): 27.209 / Net I/σ(I): 6.6 / Num. measured all: 298324
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.83-1.866.90.72921250.725100
1.86-1.96.90.6521190.744100
1.9-1.936.90.58121410.809100
1.93-1.976.90.43921260.771100
1.97-2.016.80.37621540.86100
2.01-2.066.90.31421330.801100
2.06-2.116.90.2921540.875100
2.11-2.176.90.22621540.881100
2.17-2.236.80.18721370.923100
2.23-2.316.90.1721510.962100
2.31-2.396.90.14421600.995100
2.39-2.486.80.13221441.05100
2.48-2.66.80.12321761.161100
2.6-2.736.90.11921621.46100
2.73-2.96.90.11221731.75100
2.9-3.136.90.121902.01399.9
3.13-3.4470.08922042.176100
3.44-3.9470.06322011.83100
3.94-4.9770.05822402.1399.9
4.97-506.60.05723762.17199.7

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
HKL-2000data scaling
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4GPQ

4gpq


Resolution: 1.83→40.03 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.955 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.122 / ESU R Free: 0.123 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.211 2180 5 %RANDOM
Rwork0.164 ---
obs0.166 41071 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.73 Å2
Baniso -1Baniso -2Baniso -3
1-0.97 Å20 Å20 Å2
2--0.61 Å20 Å2
3----1.58 Å2
Refinement stepCycle: LAST / Resolution: 1.83→40.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3608 0 92 266 3966
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.023824
X-RAY DIFFRACTIONr_bond_other_d00.023610
X-RAY DIFFRACTIONr_angle_refined_deg1.7341.9785196
X-RAY DIFFRACTIONr_angle_other_deg3.6053.0048271
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1065479
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.87623.593167
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.12115611
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.3111525
X-RAY DIFFRACTIONr_chiral_restr0.1130.2585
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.024303
X-RAY DIFFRACTIONr_gen_planes_other0.0170.02888
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it6.53510.2351877
X-RAY DIFFRACTIONr_mcbond_other6.53710.2281876
X-RAY DIFFRACTIONr_mcangle_it7.14315.9892345
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.83→1.88 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.28 161 -
Rwork0.236 2975 -
obs--99.94 %

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