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- PDB-5db3: Menin in complex with MI-574 -

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Basic information

Entry
Database: PDB / ID: 5db3
TitleMenin in complex with MI-574
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-58Q / DI(HYDROXYETHYL)ETHER / Menin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.71 Å
AuthorsPollock, J. / Borkin, D. / Cierpicki, T. / Grembecka, J.
Funding support United States, 8items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)1R01CA160467 United States
Leukemia & Lymphoma Society6116-12 United States
Leukemia & Lymphoma Society1215-14 United States
Leukemia & Lymphoma SocietyTherapy Acceleration Program United States
American Cancer SocietyRSG-11-082-02-DMC United States
American Cancer SocietyRSG-13-130-01-CDD United States
APS LSCAT085P100817 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 1.3Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)56,27812
Polymers54,5701
Non-polymers1,70811
Water7,188399
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.899, 80.456, 125.093
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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, 410 molecules

#2: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-58Q / 6-methoxy-4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[(4-{[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino}piperidin-1-yl)methyl]-1H-indole-2-carbonitrile


Mass: 594.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H29F3N8OS
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 399 / 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: 2.25 Å3/Da / Density % sol: 45.45 %
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-G / Wavelength: 0.97856 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 1, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 1.71→50 Å / Num. obs: 53391 / % possible obs: 98.5 % / Redundancy: 7.1 % / Rmerge(I) obs: 0.087 / Χ2: 1.65 / Net I/av σ(I): 25.778 / Net I/σ(I): 7.5 / Num. measured all: 381404
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.71-1.746.10.58925400.67895.3
1.74-1.776.50.49225980.69698.5
1.77-1.817.10.42625980.73196.5
1.81-1.847.10.37326300.76799
1.84-1.887.10.32126080.78996.6
1.88-1.937.10.27326300.84599.7
1.93-1.977.20.22826100.91197.1
1.97-2.037.20.19826310.92298.4
2.03-2.097.20.17126611.01199.1
2.09-2.157.30.14926291.07998
2.15-2.237.30.12726631.13698.3
2.23-2.327.30.11826611.33299
2.32-2.437.30.10726761.47799.4
2.43-2.557.40.09726841.43199.1
2.55-2.717.40.08526811.39698.7
2.71-2.927.50.07726971.96999.5
2.92-3.227.40.06727421.76599.7
3.22-3.687.40.0627303.04899.5
3.68-4.647.20.04827793.18799.6
4.64-506.80.05129436.96299.6

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
HKL-2000data scaling
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
RefinementResolution: 1.71→41.82 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.945 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.098 / ESU R Free: 0.097 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1941 2712 5.1 %RANDOM
Rwork0.161 ---
obs0.1627 50618 98.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 70.12 Å2 / Biso mean: 18.618 Å2 / Biso min: 8.06 Å2
Baniso -1Baniso -2Baniso -3
1--0.74 Å2-0 Å20 Å2
2--1.12 Å2-0 Å2
3----0.38 Å2
Refinement stepCycle: final / Resolution: 1.71→41.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3620 0 107 399 4126
Biso mean--30.87 30.75 -
Num. residues----467
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.023819
X-RAY DIFFRACTIONr_bond_other_d00.023606
X-RAY DIFFRACTIONr_angle_refined_deg1.6841.9845180
X-RAY DIFFRACTIONr_angle_other_deg3.6273.0088258
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6965468
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.51723.758165
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.86715607
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.2611523
X-RAY DIFFRACTIONr_chiral_restr0.1030.2579
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.024269
X-RAY DIFFRACTIONr_gen_planes_other0.0180.02879
X-RAY DIFFRACTIONr_mcbond_it1.6861.681868
X-RAY DIFFRACTIONr_mcbond_other1.6851.6811869
X-RAY DIFFRACTIONr_mcangle_it2.6252.5142331
LS refinement shellResolution: 1.711→1.755 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.27 165 -
Rwork0.224 3596 -
all-3761 -
obs--95.75 %

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