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- PDB-4gq6: Human menin in complex with MLL peptide -

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Basic information

Entry
Database: PDB / ID: 4gq6
TitleHuman menin in complex with MLL peptide
Components
  • Histone-lysine N-methyltransferase MLL
  • Menin
KeywordsTRANSCRIPTION/TRANSCRIPTION inhibitor / Tumor Suppressor / Nucleus / TRANSCRIPTION-TRANSCRIPTION inhibitor complex
Function / homology
Function and homology information


protein-cysteine methyltransferase activity / Y-form DNA binding / response to potassium ion / [histone H3]-lysine4 N-methyltransferase / histone H3K4 monomethyltransferase activity / unmethylated CpG binding / histone H3K4 trimethyltransferase activity / negative regulation of telomerase activity / negative regulation of DNA methylation-dependent heterochromatin formation / negative regulation of cyclin-dependent protein serine/threonine kinase activity ...protein-cysteine methyltransferase activity / Y-form DNA binding / response to potassium ion / [histone H3]-lysine4 N-methyltransferase / histone H3K4 monomethyltransferase activity / unmethylated CpG binding / histone H3K4 trimethyltransferase activity / negative regulation of telomerase activity / negative regulation of DNA methylation-dependent heterochromatin formation / negative regulation of cyclin-dependent protein serine/threonine kinase activity / negative regulation of JNK cascade / regulation of short-term neuronal synaptic plasticity / MLL1/2 complex / T-helper 2 cell differentiation / definitive hemopoiesis / histone H3K4 methyltransferase activity / osteoblast development / embryonic hemopoiesis / anterior/posterior pattern specification / exploration behavior / histone methyltransferase complex / Formation of WDR5-containing histone-modifying complexes / positive regulation of transforming growth factor beta receptor signaling pathway / minor groove of adenine-thymine-rich DNA binding / membrane depolarization / R-SMAD binding / cleavage furrow / MLL1 complex / negative regulation of cell cycle / RHO GTPases activate IQGAPs / negative regulation of osteoblast differentiation / four-way junction DNA binding / response to UV / negative regulation of fibroblast proliferation / homeostasis of number of cells within a tissue / transcription initiation-coupled chromatin remodeling / spleen development / cellular response to transforming growth factor beta stimulus / transcription repressor complex / Transferases; Transferring one-carbon groups; Methyltransferases / post-embryonic development / negative regulation of protein phosphorylation / Deactivation of the beta-catenin transactivating complex / response to gamma radiation / phosphoprotein binding / Post-translational protein phosphorylation / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / Formation of the beta-catenin:TCF transactivating complex / circadian regulation of gene expression / lysine-acetylated histone binding / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / visual learning / protein modification process / negative regulation of DNA-binding transcription factor activity / PKMTs methylate histone lysines / nuclear matrix / Transcriptional regulation of granulopoiesis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / MAPK cascade / protein-macromolecule adaptor activity / RUNX1 regulates transcription of genes involved in differentiation of HSCs / fibroblast proliferation / methylation / double-stranded DNA binding / protein-containing complex assembly / 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 / apoptotic process / DNA damage response / chromatin binding / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Menin / Menin / KMT2A, ePHD domain / KMT2A, PHD domain 1 / KMT2A, PHD domain 2 / KMT2A, PHD domain 3 / Methyltransferase, trithorax / : / FY-rich, N-terminal / F/Y-rich N-terminus ...Menin / Menin / KMT2A, ePHD domain / KMT2A, PHD domain 1 / KMT2A, PHD domain 2 / KMT2A, PHD domain 3 / Methyltransferase, trithorax / : / FY-rich, N-terminal / F/Y-rich N-terminus / PHD-like zinc-binding domain / FYR domain FYRN motif profile. / "FY-rich" domain, N-terminal region / FY-rich, C-terminal / F/Y rich C-terminus / FYR domain FYRC motif profile. / "FY-rich" domain, C-terminal region / CXXC zinc finger domain / Zinc finger, CXXC-type / Zinc finger CXXC-type profile. / Cysteine-rich motif following a subset of SET domains / Post-SET domain / Post-SET domain profile. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain / Extended PHD (ePHD) domain / Extended PHD (ePHD) domain profile. / SET domain profile. / SET domain / PHD-finger / Zinc finger PHD-type signature. / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Zinc finger, PHD-type / PHD zinc finger / Zinc finger, FYVE/PHD-type / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Menin / Histone-lysine N-methyltransferase 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 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 1.2Apr 16, 2014Group: Other
Revision 1.3Feb 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
B: Histone-lysine N-methyltransferase MLL
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7407
Polymers55,9752
Non-polymers7655
Water8,629479
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2580 Å2
ΔGint-54 kcal/mol
Surface area20760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.601, 80.056, 124.551
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: Protein/peptide Histone-lysine N-methyltransferase MLL / ALL-1 / CXXC-type zinc finger protein 7 / Lysine N-methyltransferase 2A / KMT2A / Trithorax-like ...ALL-1 / CXXC-type zinc finger protein 7 / Lysine N-methyltransferase 2A / KMT2A / Trithorax-like protein / Zinc finger protein HRX / MLL cleavage product N320 / N-terminal cleavage product of 320 kDa / p320 / MLL cleavage product C180 / C-terminal cleavage product of 180 kDa / p180


Mass: 1404.599 Da / Num. of mol.: 1 / Fragment: unp residues 6-15 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: Q03164, histone-lysine N-methyltransferase
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400 / Polyethylene glycol


Mass: 238.278 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 479 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE CRYSTALLIZED SEQUENCE CORRESPONDING 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: 2.16 Å3/Da / Density % sol: 43.17 %
Crystal growTemperature: 283 K / Method: 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), 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, 1:1 molar ratio with MBM1 peptide, VAPOR DIFFUSION, SITTING DROP, temperature 283K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.55→50 Å / Num. obs: 70700 / % possible obs: 98.5 % / Redundancy: 4.9 % / Rsym value: 0.076 / Net I/σ(I): 26.4
Reflection shellResolution: 1.55→1.58 Å / Redundancy: 4.5 % / Mean I/σ(I) obs: 2.1 / Rsym value: 0.583 / % possible all: 97

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Processing

SoftwareName: REFMAC / Version: 5.6.0117 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.55→50 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.961 / SU B: 2.847 / SU ML: 0.049 / Cross valid method: THROUGHOUT / ESU R: 0.075 / ESU R Free: 0.076 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.18855 3552 5 %RANDOM
Rwork0.15993 ---
obs0.16137 66808 98.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 24.471 Å2
Baniso -1Baniso -2Baniso -3
1-1.51 Å20 Å20 Å2
2---0.58 Å20 Å2
3----0.93 Å2
Refinement stepCycle: LAST / Resolution: 1.55→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3769 0 34 479 4282
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.023928
X-RAY DIFFRACTIONr_bond_other_d0.0070.022662
X-RAY DIFFRACTIONr_angle_refined_deg1.9251.9635331
X-RAY DIFFRACTIONr_angle_other_deg1.08136468
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8175490
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.44423.444180
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.20415652
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9831529
X-RAY DIFFRACTIONr_chiral_restr0.1220.2594
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.024355
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02835
LS refinement shellResolution: 1.55→1.59 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.25 259 -
Rwork0.215 4565 -
obs--98.05 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.6776-0.06150.04630.28420.34081.02280.02380.1137-0.03460.0141-0.02090.01140.12920.0008-0.00290.05440.0097-0.00530.041-0.01870.0352-5.3239-3.60324.1176
21.2344-0.89150.81982.76950.00242.5213-0.0416-0.02330.08770.11810.004-0.0570.09330.06570.03760.05680.0095-0.00050.0297-0.01370.0395-3.08459.001425.0214
30.6469-0.45560.18260.81820.27460.79110.04790.07360.0107-0.0135-0.1420.10560.0218-0.12260.09420.0113-0.01060.00930.0648-0.0290.0603-20.59718.77711.6963
40.5621-0.539-0.08931.03320.10580.5883-0.00950.0568-0.03740.0365-0.02730.0401-0.017-0.04340.03680.0078-0.0008-0.00560.0401-0.01530.0477-14.971230.465924.2518
51.78261.23190.43521.63570.43090.1302-0.11250.00340.1721-0.23520.05830.1619-0.04750.01420.05410.0967-0.0185-0.03720.0423-0.00510.0754-5.887740.028631.5662
60.0476-0.4238-0.54453.95055.07276.51390.08590.02260.0224-0.5276-0.0073-0.0824-0.6824-0.0448-0.07860.1520.00770.02150.20210.08690.1748-9.175414.88516.5582
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 211
2X-RAY DIFFRACTION2A212 - 228
3X-RAY DIFFRACTION3A229 - 332
4X-RAY DIFFRACTION4A333 - 554
5X-RAY DIFFRACTION5A555 - 587
6X-RAY DIFFRACTION6B4 - 15

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