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- PDB-5ddd: menin in complex with MI-836 -

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Basic information

Entry
Database: PDB / ID: 5ddd
Titlemenin in complex with MI-836
ComponentsMenin
KeywordsPROTEIN BINDING/INHIBITOR / PROTEIN BINDING / 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
Chem-59X / DI(HYDROXYETHYL)ETHER / Menin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.14 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

Downloads & links

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Assembly

Deposited unit
A: Menin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,94712
Polymers54,5701
Non-polymers1,37711
Water2,360131
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.307, 79.713, 124.811
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
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, 142 molecules

#2: Chemical ChemComp-59X / 4-[4-(5,5-dimethyl-4,5-dihydro-1,3-thiazol-2-yl)piperazin-1-yl]-6-(2-fluoroethyl)thieno[2,3-d]pyrimidine / MI-836


Mass: 379.518 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H22FN5S2
#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-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 131 / 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: 44.15 %
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: Apr 10, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.14→50 Å / Num. obs: 26687 / % possible obs: 98 % / Redundancy: 6.7 % / Rmerge(I) obs: 0.148 / Χ2: 1.116 / Net I/av σ(I): 15.339 / Net I/σ(I): 4.9 / Num. measured all: 179804
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.14-2.186.40.82413120.82197
2.18-2.226.60.75213050.77796.4
2.22-2.266.80.66512910.7398.5
2.26-2.316.80.63212960.73296.3
2.31-2.366.80.52612930.76897.4
2.36-2.416.70.47712940.7796
2.41-2.476.80.43612910.74197.6
2.47-2.546.70.40213170.79996.8
2.54-2.616.80.33712940.78497.4
2.61-2.76.80.30313020.86596.7
2.7-2.796.70.25513190.88398.4
2.79-2.96.80.2113200.92897.2
2.9-3.046.80.18413340.94597.9
3.04-3.26.70.1513501.06998.8
3.2-3.46.80.12813311.19499.3
3.4-3.666.70.10613581.50599.6
3.66-4.036.90.09513901.79699.6
4.03-4.616.90.07913771.82699.9
4.61-5.8170.07714111.699.9
5.81-506.30.08315022.45699.3

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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: 2.14→41.35 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.919 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.275 / ESU R Free: 0.212 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.248 1335 5 %RANDOM
Rwork0.201 ---
obs0.203 25300 97.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 50.24 Å2
Baniso -1Baniso -2Baniso -3
1-2.4 Å20 Å20 Å2
2---0.78 Å20 Å2
3----1.63 Å2
Refinement stepCycle: LAST / Resolution: 2.14→41.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3615 0 81 131 3827
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0193785
X-RAY DIFFRACTIONr_bond_other_d00.023565
X-RAY DIFFRACTIONr_angle_refined_deg1.7141.9765135
X-RAY DIFFRACTIONr_angle_other_deg3.6113.0048157
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8795466
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.9123.713167
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.29415597
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.3631524
X-RAY DIFFRACTIONr_chiral_restr0.0990.2576
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.024261
X-RAY DIFFRACTIONr_gen_planes_other0.0140.02878
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_it3.0375.0641870
X-RAY DIFFRACTIONr_mcbond_other3.0375.0631869
X-RAY DIFFRACTIONr_mcangle_it5.0087.5742334
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: 2.14→2.2 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.351 85 -
Rwork0.279 1813 -
obs--94.15 %

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