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- PDB-6kix: Cryo-EM structure of human MLL1-NCP complex, binding mode1 -

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Entry
Database: PDB / ID: 6kix
TitleCryo-EM structure of human MLL1-NCP complex, binding mode1
Components
  • (DNA (145-MER)) x 2
  • Histone H2A
  • Histone H2B 1.1
  • Histone H3
  • Histone H4
  • Histone-lysine N-methyltransferase 2A
  • Retinoblastoma-binding protein 5
  • Set1/Ash2 histone methyltransferase complex subunit ASH2
  • WD repeat-containing protein 5
KeywordsTRANSCRIPTION/DNA / histone modification / nucleosome / MLL / TRANSCRIPTION / TRANSCRIPTION-DNA complex
Function / homology
Function and homology information


RMTs methylate histone arginines / Formation of the beta-catenin:TCF transactivating complex / PKMTs methylate histone lysines / HATs acetylate histones / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Neddylation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Deactivation of the beta-catenin transactivating complex / euchromatin binding ...RMTs methylate histone arginines / Formation of the beta-catenin:TCF transactivating complex / PKMTs methylate histone lysines / HATs acetylate histones / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Neddylation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Deactivation of the beta-catenin transactivating complex / euchromatin binding / regulation of histone H3-K14 acetylation / positive regulation of cellular response to drug / positive regulation of transporter activity / negative regulation of DNA methylation / unmethylated CpG binding / histone methyltransferase activity (H3-K4 specific) / histone H3-K4 trimethylation / Set1C/COMPASS complex / MLL3/4 complex / AT DNA binding / positive regulation of gluconeogenesis by positive regulation of transcription from RNA polymerase II promoter / histone H4-K5 acetylation / histone H4-K8 acetylation / histone H3-K4 methylation / Ada2/Gcn5/Ada3 transcription activator complex / regulation of histone H3-K9 acetylation / histone H4-K16 acetylation / positive regulation of histone H3-K4 methylation / MLL1 complex / embryonic hemopoiesis / beta-catenin-TCF complex assembly / nuclear euchromatin / hemopoiesis / histone acetyltransferase complex / histone-lysine N-methyltransferase / regulation of hematopoietic stem cell differentiation / histone H3 acetylation / DNA-templated transcription, initiation / methylated histone binding / lysine-acetylated histone binding / histone methyltransferase complex / RNA polymerase II distal enhancer sequence-specific DNA binding / skeletal system development / regulation of megakaryocyte differentiation / nucleosome / circadian regulation of gene expression / neuron projection development / beta-catenin binding / protein-containing complex assembly / post-translational protein modification / transcription by RNA polymerase II / histone binding / transcription regulatory region DNA binding / response to estrogen / transcription, DNA-templated / DNA-binding transcription factor activity, RNA polymerase II-specific / apoptotic process / cellular response to DNA damage stimulus / regulation of transcription, DNA-templated / DNA-binding transcription factor activity / nucleolus / positive regulation of cell population proliferation / protein heterodimerization activity / positive regulation of transcription, DNA-templated / positive regulation of transcription by RNA polymerase II / protein homodimerization activity / DNA binding / zinc ion binding / nucleoplasm / identical protein binding / metal ion binding / nucleus / cytosol
Post-SET domain / WD40 repeat / FY-rich, C-terminal / FY-rich, N-terminal / SPRY domain / Zinc finger, CXXC-type / Histone H2A / Zinc finger, PHD-type / Histone H4 / B30.2/SPRY domain ...Post-SET domain / WD40 repeat / FY-rich, C-terminal / FY-rich, N-terminal / SPRY domain / Zinc finger, CXXC-type / Histone H2A / Zinc finger, PHD-type / Histone H4 / B30.2/SPRY domain / Bromodomain / Histone H2A/H2B/H3 / SET domain / Histone H2B / Histone H3/CENP-A / KMT2A, PHD domain 2 / Core histone H2A/H2B/H3/H4 / WD domain, G-beta repeat / KMT2A, PHD domain 1 / SPRY domain / PHD-finger / TATA box binding protein associated factor (TAF) / Histone-fold / CXXC zinc finger domain / Histone H2A conserved site / Histone-lysine N-methyltransferase 2A / WD40-repeat-containing protein Swd3/WDR5 / Retinoblastoma-binding protein 5/Swd1 / Histone methyltransferase complex subunit ASH2 / Bromodomain-like superfamily / WD40-repeat-containing domain superfamily / CENP-T/Histone H4, histone fold / Extended PHD (ePHD) domain / Histone H2A, C-terminal domain / Zinc finger, FYVE/PHD-type / G-protein beta WD-40 repeat / Histone H4, conserved site / Zinc finger, PHD-finger / WD40 repeat, conserved site / WD40-repeat-containing domain / Methyltransferase, trithorax / WD40/YVTN repeat-like-containing domain superfamily / Concanavalin A-like lectin/glucanase domain superfamily / Zinc finger, RING/FYVE/PHD-type / SET domain / KMT2A, ePHD domain / F/Y-rich N-terminus / Trp-Asp (WD) repeats profile. / Histone H2B signature. / Trp-Asp (WD) repeats signature. / Histone H3 signature 2. / Zinc finger PHD-type signature. / Bromodomain profile. / Zinc finger PHD-type profile. / B30.2/SPRY domain profile. / Histone H3 signature 1. / SET domain profile. / Trp-Asp (WD) repeats circular profile. / Post-SET domain profile. / Zinc finger CXXC-type profile. / FYR domain FYRN motif profile. / FYR domain FYRC motif profile. / Extended PHD (ePHD) domain profile. / Histone H4 signature. / F/Y rich C-terminus / Histone H2A signature. / Centromere kinetochore component CENP-T histone fold / C-terminus of histone H2A
Histone H3 / Histone H2B 1.1 / WD repeat-containing protein 5 / Histone H4 / Histone-lysine N-methyltransferase 2A / Retinoblastoma-binding protein 5 / Histone H2A / Set1/Ash2 histone methyltransferase complex subunit ASH2
Biological speciesXenopus laevis (African clawed frog)
Homo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsHuang, J. / Xue, H. / Yao, T.
Funding support China, 1items
OrganizationGrant numberCountry
National Science Foundation (China) China
CitationJournal: Nature / Year: 2019
Title: Structural basis of nucleosome recognition and modification by MLL methyltransferases.
Authors: Han Xue / Tonghui Yao / Mi Cao / Guanjun Zhu / Yan Li / Guiyong Yuan / Yong Chen / Ming Lei / Jing Huang /
Abstract: Methyltransferases of the mixed-lineage leukaemia (MLL) family-which include MLL1, MLL2, MLL3, MLL4, SET1A and SET1B-implement methylation of histone H3 on lysine 4 (H3K4), and have critical and ...Methyltransferases of the mixed-lineage leukaemia (MLL) family-which include MLL1, MLL2, MLL3, MLL4, SET1A and SET1B-implement methylation of histone H3 on lysine 4 (H3K4), and have critical and distinct roles in the regulation of transcription in haematopoiesis, adipogenesis and development. The C-terminal catalytic SET (Su(var.)3-9, enhancer of zeste and trithorax) domains of MLL proteins are associated with a common set of regulatory factors (WDR5, RBBP5, ASH2L and DPY30) to achieve specific activities. Current knowledge of the regulation of MLL activity is limited to the catalysis of histone H3 peptides, and how H3K4 methyl marks are deposited on nucleosomes is poorly understood. H3K4 methylation is stimulated by mono-ubiquitination of histone H2B on lysine 120 (H2BK120ub1), a prevalent histone H2B mark that disrupts chromatin compaction and favours open chromatin structures, but the underlying mechanism remains unknown. Here we report cryo-electron microscopy structures of human MLL1 and MLL3 catalytic modules associated with nucleosome core particles that contain H2BK120ub1 or unmodified H2BK120. These structures demonstrate that the MLL1 and MLL3 complexes both make extensive contacts with the histone-fold and DNA regions of the nucleosome; this allows ease of access to the histone H3 tail, which is essential for the efficient methylation of H3K4. The H2B-conjugated ubiquitin binds directly to RBBP5, orienting the association between MLL1 or MLL3 and the nucleosome. The MLL1 and MLL3 complexes display different structural organizations at the interface between the WDR5, RBBP5 and MLL1 (or the corresponding MLL3) subunits, which accounts for the opposite roles of WDR5 in regulating the activity of the two enzymes. These findings transform our understanding of the structural basis for the regulation of MLL activity at the nucleosome level, and highlight the pivotal role of nucleosome regulation in histone-tail modification.
Validation Report
SummaryFull reportAbout validation report
History
DepositionJul 20, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 11, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 18, 2019Group: Data collection / Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

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Assembly

Deposited unit
A: Histone H3
B: Histone H4
C: Histone H2A
D: Histone H2B 1.1
E: Histone H3
F: Histone H4
G: Histone H2A
H: Histone H2B 1.1
I: DNA (145-MER)
J: DNA (145-MER)
N: Retinoblastoma-binding protein 5
K: Histone-lysine N-methyltransferase 2A
R: WD repeat-containing protein 5
T: Set1/Ash2 histone methyltransferase complex subunit ASH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)379,46418
Polymers378,72014
Non-polymers7434
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein/peptide , 8 types, 12 molecules AEBFCGDHNKRT

#1: Protein/peptide Histone H3 /


Mass: 15303.930 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: XELAEV_18002543mg / Production host: Escherichia coli (E. coli) / References: UniProt: A0A310TTQ1
#2: Protein/peptide Histone H4 /


Mass: 11263.231 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli) / References: UniProt: P62799
#3: Protein/peptide Histone H2A /


Mass: 13978.241 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: hist1h2aj, LOC494591, XELAEV_18003602mg / Production host: Escherichia coli (E. coli) / References: UniProt: Q6AZJ8
#4: Protein/peptide Histone H2B 1.1 / H2B1.1


Mass: 13498.715 Da / Num. of mol.: 2 / Mutation: S29T/K117C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Production host: Escherichia coli (E. coli) / References: UniProt: P02281
#7: Protein/peptide Retinoblastoma-binding protein 5 / RBBP-5 / Retinoblastoma-binding protein RBQ-3


Mass: 59223.477 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RBBP5, RBQ3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15291
#8: Protein/peptide Histone-lysine N-methyltransferase 2A / Lysine N-methyltransferase 2A / ALL-1 / CXXC-type zinc finger protein 7 / Myeloid/lymphoid or mixed-lineage leukemia / Myeloid/lymphoid or mixed-lineage leukemia protein 1 / Trithorax-like protein / Zinc finger protein HRX


Mass: 24970.539 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KMT2A, ALL1, CXXC7, HRX, HTRX, MLL, MLL1, TRX1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q03164, histone-lysine N-methyltransferase
#9: Protein/peptide WD repeat-containing protein 5 / BMP2-induced 3-kb gene protein


Mass: 36635.438 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR5, BIG3 / Production host: Escherichia coli (E. coli) / References: UniProt: P61964
#10: Protein/peptide Set1/Ash2 histone methyltransferase complex subunit ASH2 / ASH2-like protein


Mass: 60288.758 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ASH2L, ASH2L1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UBL3

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DNA chain , 2 types, 2 molecules IJ

#5: DNA chain DNA (145-MER)


Mass: 44521.367 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: DNA chain DNA (145-MER)


Mass: 44992.648 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 4 types, 4 molecules

#11: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE


Mass: 384.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20N6O5S / S-Adenosyl-L-homocysteine
#12: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Zinc
#13: Chemical ChemComp-LYS / LYSINE


Mass: 147.195 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H15N2O2 / Lysine
#14: Chemical ChemComp-GLN / GLUTAMINE


Mass: 146.144 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H10N2O3 / Glutamine

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component

Type: COMPLEX

IDNameEntity IDParent-IDSource
1Human MLL1 complex associated with an unmodified nucleosome, binding mode 11,2,3,4,5,6,7,8,9,100MULTIPLE SOURCES
2Human MLL1 complexKMT2A7,8,9,101RECOMBINANT
3unmodified nucleosome1,2,3,4,5,61MULTIPLE SOURCES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Xenopus laevis (African clawed frog)8355
Source (recombinant)

Ncbi tax-ID: 562 / Organism: Escherichia coli (E. coli)

IDEntity assembly-ID
12
23
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 45 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.13_2998refinement
PHENIX1.13_2998refinement
CTF correctionType: PHASE FLIPPING ONLY
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 21279 / Symmetry type: POINT
RefinementStereochemistry target values: GeoStd + Monomer Library
Refine LS restraints

Refinement-ID: ELECTRON MICROSCOPY

TypeDev idealNumber
f_bond_d0.005620888
f_angle_d0.819729470
f_chiral_restr0.05023307
f_plane_restr0.00682727
f_dihedral_angle_d19.089111518

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