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- PDB-5dde: Menin in complex with MI-859 -

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Basic information

Entry
Database: PDB / ID: 5dde
TitleMenin in complex with MI-859
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
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.78 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 Society6116-12 United States
Leukemia & Lymphoma Society1215-14 United States
Department of Energy (DOE, United States)DE-AC02-06CH11357 United States
LS-CAT 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

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Assembly

Deposited unit
A: Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,31813
Polymers54,5701
Non-polymers1,74812
Water6,377354
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.705, 79.713, 124.644
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, 366 molecules

#2: Chemical ChemComp-5A0 / 6-(2,2-difluoroethyl)-4-[4-(5,5-dimethyl-4,5-dihydro-1,3-thiazol-2-yl)piperazin-1-yl]thieno[2,3-d]pyrimidine / MI-859


Mass: 397.509 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H21F2N5S2
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 354 / 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: 2.22 Å3/Da / Density % sol: 44.54 %
Crystal growTemperature: 283 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: Jun 2, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.78→50 Å / Num. obs: 47042 / % possible obs: 99.4 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.102 / Χ2: 1.22 / Net I/av σ(I): 20.968 / Net I/σ(I): 6.4 / Num. measured all: 311806
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.78-1.816.40.71223020.99698.1
1.81-1.846.40.60922451.04398.3
1.84-1.886.40.53423250.96898.3
1.88-1.926.40.46422850.96898.9
1.92-1.966.40.38422980.98298.8
1.96-26.40.3323230.97699
2-2.056.50.28123120.96899.4
2.05-2.116.50.2523550.98699.5
2.11-2.176.50.21423061.06799.6
2.17-2.246.50.18223351.07899.4
2.24-2.326.60.1623571.06799.7
2.32-2.426.60.14323371.12699.6
2.42-2.536.60.12823361.12799.7
2.53-2.666.70.12123641.21799.8
2.66-2.836.80.1123671.438100
2.83-3.046.90.09723861.529100
3.04-3.357.10.08123771.618100
3.35-3.837.20.06324031.525100
3.83-4.8370.05824501.707100
4.83-506.70.05725791.69799.8

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Processing

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

4gpq


Resolution: 1.78→41.6 Å / Cross valid method: THROUGHOUT / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.199 2376 5.1 %RANDOM
Rwork0.171 ---
obs-44545 99.1 %-
Displacement parametersBiso mean: 22.42 Å2
Baniso -1Baniso -2Baniso -3
1-1.23 Å20 Å2-0 Å2
2---0.44 Å2-0 Å2
3----0.78 Å2
Refinement stepCycle: LAST / Resolution: 1.78→41.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3636 0 105 354 4095
LS refinement shellResolution: 1.78→1.83 Å
RfactorNum. reflection% reflection
Rfree0.246 162 -
Rwork0.222 3103 -
obs--94.2 %

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