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- PDB-4gpq: Structural insights into inhibition of the bivalent menin-MLL int... -

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Basic information

Entry
Database: PDB / ID: 4gpq
TitleStructural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia
ComponentsMenin
KeywordsTRANSCRIPTION / Tumor Suppressor / Nucleus
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 / negative regulation of protein phosphorylation / transcription initiation-coupled chromatin remodeling / response to gamma radiation / Deactivation of the beta-catenin transactivating complex / Post-translational protein phosphorylation / 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 / 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
DI(HYDROXYETHYL)ETHER / Menin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.46 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 21, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 19, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 2, 2013Group: Database references
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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)55,2155
Polymers54,5701
Non-polymers6454
Water10,557586
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)48.812, 80.178, 124.686
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#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
#2: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#3: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#4: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 586 / Source method: isolated from a natural source / Formula: H2O
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: 2.24 Å3/Da / Density % sol: 44.98 %
Crystal growMethod: vapor diffusion, sitting drop / pH: 7.5
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

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Data collection

Diffraction
IDCrystal-ID
11
21
Diffraction source
SourceSiteBeamlineID
SYNCHROTRONAPS 21-ID-D1
APS 21-ID-F2
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.46→36.9 Å / Num. obs: 85179 / % possible obs: 99.4 % / Redundancy: 6.8 % / Rsym value: 0.11 / Net I/σ(I): 16.1
Reflection shellResolution: 1.46→1.49 Å / Redundancy: 5.6 % / Mean I/σ(I) obs: 4.5 / Rsym value: 0.361 / % possible all: 88.1

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Processing

SoftwareName: REFMAC / Version: 5.6.0119 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3RE2

3re2


Resolution: 1.46→36.9 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.963 / SU B: 1.754 / SU ML: 0.034 / Cross valid method: THROUGHOUT / ESU R: 0.069 / ESU R Free: 0.062 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.17555 4236 5 %RANDOM
Rwork0.14459 ---
obs0.14617 80382 99.31 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 18.124 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å20 Å20 Å2
2--0.05 Å20 Å2
3----0.04 Å2
Refinement stepCycle: LAST / Resolution: 1.46→36.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3689 0 42 586 4317
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0223969
X-RAY DIFFRACTIONr_angle_refined_deg1.1921.9675395
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.065503
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.5123.913184
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.54315675
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.5221527
X-RAY DIFFRACTIONr_chiral_restr0.0830.2593
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213020
X-RAY DIFFRACTIONr_rigid_bond_restr3.25633928
X-RAY DIFFRACTIONr_sphericity_bonded12.79653829
LS refinement shellResolution: 1.463→1.501 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.245 287 -
Rwork0.205 5331 -
obs--94.82 %

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