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- PDB-5db0: Menin in complex with MI-352 -

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Basic information

Entry
Database: PDB / ID: 5db0
TitleMenin in complex with MI-352
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 / MLL1/2 complex / T-helper 2 cell differentiation / osteoblast development / histone methyltransferase complex / negative regulation of telomerase activity / 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 / MLL1/2 complex / T-helper 2 cell differentiation / osteoblast development / histone methyltransferase complex / negative regulation of telomerase activity / Formation of WDR5-containing histone-modifying complexes / positive regulation of transforming growth factor beta receptor signaling pathway / MLL1 complex / R-SMAD binding / cleavage furrow / negative regulation of cell cycle / RHO GTPases activate IQGAPs / negative regulation of osteoblast differentiation / four-way junction DNA binding / response to UV / transcription initiation-coupled chromatin remodeling / transcription repressor complex / negative regulation of protein phosphorylation / Deactivation of the beta-catenin transactivating complex / Post-translational protein phosphorylation / response to gamma radiation / 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 / endoplasmic reticulum lumen / negative regulation of cell population proliferation / 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-58P / Chem-6E6 / Menin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsPollock, J. / Dmitry, B. / Cierpicki, T. / Grembecka, J.
Funding support United States, 7items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)1R)1CA160467 United States
Leukemia & Lymphoma Society6116-12 United States
Leukemia & Lymphoma Society1215-14 United States
Leukemia & Lymphoma SocietyTherapy Accelerated Program United States
American Chemical SocietyRSG-11-082-01-DMC United States
American Chemical SocietyRSG-13-130-01-CDD United States
APS LSCAT085P1000817 United States
CitationJournal: J.Med.Chem. / Year: 2016
Title: Property Focused Structure-Based Optimization of Small Molecule Inhibitors of the Protein-Protein Interaction between Menin and Mixed Lineage Leukemia (MLL).
Authors: Borkin, D. / Pollock, J. / Kempinska, K. / Purohit, T. / Li, X. / Wen, B. / Zhao, T. / Miao, H. / Shukla, S. / He, M. / Sun, D. / Cierpicki, T. / Grembecka, J.
History
DepositionAug 20, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 30, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 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 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name

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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)56,93914
Polymers54,5701
Non-polymers2,36913
Water8,233457
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.968, 79.970, 124.479
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, 470 molecules

#2: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL / Polyethylene glycol


Mass: 194.226 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-58P / 1-[(2S)-2,3-dihydroxypropyl]-5-[(4-{[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino}piperidin-1-yl)methyl]-1 H-indole-2-carbonitrile / MI-352


Mass: 544.592 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H27F3N6O2S
#6: Chemical ChemComp-6E6 / 1-[(2R)-2,3-dihydroxypropyl]-5-[(4-{[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino}piperidin-1-yl)methyl]-1H-indole-2-carbonitrile


Mass: 544.592 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H27F3N6O2S
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 457 / 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: 2.23 Å3/Da / Density % sol: 44.92 %
Crystal growTemperature: 283 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.2 M ammonium acetate, 0.1 M HEPES pH 7.5 and 25% w/v PEG 3,350. This solution was mixed 1:1 with 2.5mg/mL protein in 50mM Tris-HCl (pH 8.0), 50mM NaCl, and 1mM TCEP. Prior to data ...Details: 0.2 M ammonium acetate, 0.1 M HEPES pH 7.5 and 25% w/v PEG 3,350. This solution was mixed 1:1 with 2.5mg/mL protein in 50mM Tris-HCl (pH 8.0), 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, VAPOR DIFFUSION, SITTING DROP, temperature 283K

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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: Oct 7, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. obs: 74950 / % possible obs: 94.8 % / Redundancy: 5.6 % / Rmerge(I) obs: 0.07 / Rpim(I) all: 0.03 / Rrim(I) all: 0.076 / Χ2: 1.112 / Net I/av σ(I): 25.148 / Net I/σ(I): 8.5 / Num. measured all: 419739
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.5-1.5350.50732990.9020.2350.5610.61384.7
1.53-1.5550.46133670.9090.2130.510.64386.7
1.55-1.5850.38633570.9220.1780.4270.63985.7
1.58-1.6250.35234590.9350.1620.3890.63788.3
1.62-1.6550.30434490.9520.1390.3360.65188.8
1.65-1.6950.27135390.9580.1240.2990.68590.2
1.69-1.7350.23535940.9650.1080.260.68792.3
1.73-1.7850.20436610.9710.0940.2260.73293
1.78-1.835.10.17337310.9780.0790.1910.73895.1
1.83-1.895.20.14937610.9830.0680.1650.80196
1.89-1.965.30.12838390.9870.0580.1410.86397.7
1.96-2.045.40.10638690.9910.0480.1170.91498.3
2.04-2.135.60.09639120.9930.0430.1061.04598.9
2.13-2.245.80.0938950.9940.0390.0981.34199.5
2.24-2.385.90.08639400.9940.0370.0941.58399.7
2.38-2.566.10.0839880.9940.0340.0871.64199.7
2.56-2.826.40.06839630.9960.0290.0741.54299.9
2.82-3.236.70.05640230.9970.0230.0611.44399.9
3.23-4.0770.04940610.9970.020.0531.68100
4.07-506.70.04642430.9970.0190.051.70399.7

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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: 1.5→40.02 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.959 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.07 / ESU R Free: 0.07 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.185 3801 5.1 %RANDOM
Rwork0.161 ---
obs0.162 71069 94.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 17.27 Å2
Baniso -1Baniso -2Baniso -3
1-1.09 Å20 Å20 Å2
2---0.16 Å20 Å2
3----0.93 Å2
Refinement stepCycle: LAST / Resolution: 1.5→40.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3621 0 142 457 4220
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.023881
X-RAY DIFFRACTIONr_bond_other_d00.023652
X-RAY DIFFRACTIONr_angle_refined_deg1.7521.9945270
X-RAY DIFFRACTIONr_angle_other_deg3.5943.018380
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6165474
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.39423.939165
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.33915617
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5221521
X-RAY DIFFRACTIONr_chiral_restr0.110.2586
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.024313
X-RAY DIFFRACTIONr_gen_planes_other0.0180.02884
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_it1.5311.5511878
X-RAY DIFFRACTIONr_mcbond_other1.5311.5521879
X-RAY DIFFRACTIONr_mcangle_it2.3412.3222345
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: 1.5→1.54 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.248 240 -
Rwork0.215 4626 -
obs--84.09 %

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