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- PDB-4gq4: Human menin with bound inhibitor MI-2-2 -

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Basic information

Entry
Database: PDB / ID: 4gq4
TitleHuman menin with bound inhibitor MI-2-2
ComponentsMenin
KeywordsTRANSCRIPTION/TRANSCRIPTION inhibitor / Tumor Suppressor / Nucleus / TRANSCRIPTION-TRANSCRIPTION inhibitor complex
Function / homology
Function and homology information


Y-form DNA binding / negative regulation of telomerase activity / 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 / Formation of WDR5-containing histone-modifying complexes / positive regulation of transforming growth factor beta receptor signaling pathway ...Y-form DNA binding / negative regulation of telomerase activity / 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 / 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
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.27 Å
AuthorsShi, A. / Murai, M.J. / He, S. / Lund, G.L. / Hartley, T. / Purohit, T. / Reddy, G. / Chruszcz, M. / Grembecka, J. / Cierpicki, T.
CitationJournal: Blood / Year: 2012
Title: Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia.
Authors: Shi, A. / Murai, M.J. / He, S. / Lund, G. / Hartley, T. / Purohit, T. / Reddy, G. / Chruszcz, M. / Grembecka, J. / Cierpicki, T.
History
DepositionAug 22, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 19, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 2, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)56,39515
Polymers54,5701
Non-polymers1,82514
Water10,701594
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.044, 80.160, 124.812
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 / 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 , 7 types, 608 molecules

#2: Chemical ChemComp-0RT / 4-[4-(5,5-dimethyl-4,5-dihydro-1,3-thiazol-2-yl)piperazin-1-yl]-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine


Mass: 415.499 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20F3N5S2
#3: Chemical
ChemComp-UNX / UNKNOWN ATOM OR ION


Num. of mol.: 5 / Source method: obtained synthetically
#4: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES / HEPES


Mass: 238.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#5: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-PE4 / 2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL / POLYETHYLENE GLYCOL PEG4000 / Polyethylene glycol


Mass: 354.436 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H34O8 / Comment: precipitant*YM
#7: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 594 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsTHE CRYSTALLIZED SEQUENCE CORRESPONDS TO THE HUMAN MENIN ISOFORM 2

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.25 Å3/Da / Density % sol: 45.28 %
Crystal growMethod: vapor diffusion, sitting drop
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), NBm1 peptide, 50mM NaCl, and 1mM TCEP. Prior to ...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), NBm1 peptide, 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, 200 mM 0RT, VAPOR DIFFUSION, SITTING DROP

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Data collection

Diffraction
IDCrystal-ID
11
21
Diffraction source
SourceSiteBeamlineID
SYNCHROTRONAPS 21-ID-D1
SYNCHROTRONAPS 21-ID-F2
Detector
TypeIDDetector
MARMOSAIC 300 mm CCD1CCD
MARMOSAIC 225 mm CCD2CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.27→40.08 Å / Num. obs: 129732 / % possible obs: 99.9 % / Redundancy: 6.2 % / Rsym value: 0.108 / Net I/σ(I): 30.6
Reflection shellResolution: 1.27→1.29 Å / Mean I/σ(I) obs: 2.4 / Rsym value: 0.646 / % possible all: 99.9

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Processing

SoftwareName: REFMAC / Version: 5.6.0117 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.27→40.08 Å / Cor.coef. Fo:Fc: 0.978 / Cor.coef. Fo:Fc free: 0.97 / Cross valid method: THROUGHOUT / ESU R: 0.046 / ESU R Free: 0.046 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.18158 6276 5 %RANDOM
Rwork0.14911 ---
obs0.15071 119332 96.44 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.565 Å2
Baniso -1Baniso -2Baniso -3
1-1.77 Å20 Å20 Å2
2--0.23 Å20 Å2
3----2 Å2
Refinement stepCycle: LAST / Resolution: 1.27→40.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3690 0 94 594 4378
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.024010
X-RAY DIFFRACTIONr_bond_other_d00.022701
X-RAY DIFFRACTIONr_angle_refined_deg1.9831.985456
X-RAY DIFFRACTIONr_angle_other_deg4.2383.0016580
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6175497
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.38123.736182
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.65215663
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.371528
X-RAY DIFFRACTIONr_chiral_restr0.1360.2601
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0214483
X-RAY DIFFRACTIONr_gen_planes_other0.0180.02838
X-RAY DIFFRACTIONr_rigid_bond_restr7.48833914
X-RAY DIFFRACTIONr_sphericity_bonded13.81753822
LS refinement shellResolution: 1.27→1.303 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.261 312 -
Rwork0.2 5683 -
obs--63.08 %

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