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- PDB-6kiu: Cryo-EM structure of human MLL1-ubNCP complex (3.2 angstrom) -

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Entry
Database: PDB / ID: 6kiu
TitleCryo-EM structure of human MLL1-ubNCP complex (3.2 angstrom)
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
  • Ubiquitin
  • WD repeat-containing protein 5
KeywordsTRANSCRIPTION/DNA / histone modification / nucleosome / MLL / TRANSCRIPTION / TRANSCRIPTION-DNA complex
Function / homology
Function and homology information


euchromatin binding / positive regulation of cellular response to drug / regulation of histone H3-K14 acetylation / positive regulation of transporter activity / negative regulation of DNA methylation / histone H3-K4 dimethylation / histone H3-K4 monomethylation / unmethylated CpG binding / histone methyltransferase activity (H3-K4 specific) / [histone H3]-lysine4 N-trimethyltransferase ...euchromatin binding / positive regulation of cellular response to drug / regulation of histone H3-K14 acetylation / positive regulation of transporter activity / negative regulation of DNA methylation / histone H3-K4 dimethylation / histone H3-K4 monomethylation / unmethylated CpG binding / histone methyltransferase activity (H3-K4 specific) / [histone H3]-lysine4 N-trimethyltransferase / histone H3-K4 trimethylation / Set1C/COMPASS complex / regulation of histone H3-K9 acetylation / MLL3/4 complex / histone H4-K5 acetylation / histone H4-K8 acetylation / Ada2/Gcn5/Ada3 transcription activator complex / minor groove of adenine-thymine-rich DNA binding / histone H3-K4 methylation / histone H4-K16 acetylation / embryonic hemopoiesis / negative regulation of histone H3-K4 methylation / MLL1 complex / beta-catenin-TCF complex assembly / positive regulation of gluconeogenesis / nuclear euchromatin / positive regulation of histone H3-K4 methylation / SRP-dependent cotranslational protein targeting to membrane / hemopoiesis / regulation of hematopoietic stem cell differentiation / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / viral transcription / histone acetyltransferase complex / histone H3 acetylation / translational initiation / MyD88-independent toll-like receptor signaling pathway / histone methyltransferase complex / nucleotide-binding oligomerization domain containing signaling pathway / nucleotide-excision repair, DNA gap filling / nucleotide-excision repair, DNA damage recognition / methylated histone binding / nucleotide-excision repair, DNA duplex unwinding / TRIF-dependent toll-like receptor signaling pathway / DNA-templated transcription, initiation / global genome nucleotide-excision repair / host cell / nucleotide-excision repair, preincision complex assembly / lysine-acetylated histone binding / intracellular transport of virus / MyD88-dependent toll-like receptor signaling pathway / nucleotide-excision repair, DNA incision, 5'-to lesion / endosomal transport / regulation of megakaryocyte differentiation / DNA damage response, detection of DNA damage / skeletal system development / error-free translesion synthesis / nucleotide-excision repair, DNA incision / modification-dependent protein catabolic process / protein targeting to peroxisome / JNK cascade / circadian regulation of gene expression / nucleosome / interstrand cross-link repair / endocytic vesicle membrane / protein tag / stress-activated MAPK cascade / error-prone translesion synthesis / interleukin-1-mediated signaling pathway / regulation of transcription from RNA polymerase II promoter in response to hypoxia / I-kappaB kinase/NF-kappaB signaling / neuron projection development / transcription-coupled nucleotide-excision repair / viral life cycle / negative regulation of transforming growth factor beta receptor signaling pathway / beta-catenin binding / translesion synthesis / transforming growth factor beta receptor signaling pathway / anaphase-promoting complex-dependent catabolic process / virion assembly / cytosolic small ribosomal subunit / transmembrane transport / regulation of mRNA stability / small ribosomal subunit / protein-containing complex assembly / post-translational protein modification / membrane organization / protein polyubiquitination / histone binding / Wnt signaling pathway / mitochondrial outer membrane / vesicle / activation of MAPK activity / structural constituent of ribosome / response to estrogen / endosome membrane / transcription regulatory region sequence-specific DNA binding / positive regulation of NF-kappaB transcription factor activity / protein ubiquitination / protein deubiquitination / translation
Ubiquitin conserved site / KMT2A, PHD domain 1 / Bromodomain / Histone-lysine N-methyltransferase 2A / Ubiquitin-like domain / Histone H2B / C-terminus of histone H2A / Histone H3/CENP-A / Core histone H2A/H2B/H3/H4 / Centromere kinetochore component CENP-T histone fold ...Ubiquitin conserved site / KMT2A, PHD domain 1 / Bromodomain / Histone-lysine N-methyltransferase 2A / Ubiquitin-like domain / Histone H2B / C-terminus of histone H2A / Histone H3/CENP-A / Core histone H2A/H2B/H3/H4 / Centromere kinetochore component CENP-T histone fold / G-protein beta WD-40 repeat / Ubiquitin-like domain superfamily / KMT2A, PHD domain 2 / Histone H2A, C-terminal domain / B30.2/SPRY domain / Histone H2A conserved site / KMT2A, ePHD domain / Extended PHD (ePHD) domain / CENP-T/Histone H4, histone fold / WD40-repeat-containing domain superfamily / Bromodomain-like superfamily / Histone methyltransferase complex subunit ASH2 / S27a-like superfamily / Retinoblastoma-binding protein 5/Swd1 / Ubiquitin domain / in:ipr037866: / WD40 repeat / SET domain / SET domain / FY-rich, N-terminal / 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 / Zinc-binding ribosomal protein / Zinc finger, FYVE/PHD-type / Histone-fold / Histone H2A/H2B/H3 / TATA box binding protein associated factor (TAF) / WD domain, G-beta repeat / FY-rich, C-terminal / SPRY domain / Ribosomal protein S27a / Ubiquitin family / Post-SET domain / Histone H4 / SPRY domain / Zinc finger, PHD-type / Histone H2A / Zinc finger, CXXC-type / SPRY domain / Histone, subunit A / Histone, subunit A / YVTN repeat-like/Quinoprotein amine dehydrogenase / Methylamine Dehydrogenase; Chain H / 7 Propeller / Jelly Rolls / Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Ubiquitin-40S ribosomal protein S27a / Histone H4 / Histone H3 / Histone H2B 1.1 / Histone H2A type 1 / WD repeat-containing protein 5 / Set1/Ash2 histone methyltransferase complex subunit ASH2 / Histone H2A / Retinoblastoma-binding protein 5 / Histone-lysine N-methyltransferase 2A / Histone H3.2
Biological speciesXenopus laevis (African clawed frog)
Homo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 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
Revision 1.2Oct 2, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Nov 6, 2019Group: Data collection / Other / Category: cell / Item: _cell.Z_PDB

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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)
K: Histone-lysine N-methyltransferase 2A
N: Retinoblastoma-binding protein 5
R: WD repeat-containing protein 5
T: Set1/Ash2 histone methyltransferase complex subunit ASH2
O: Ubiquitin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)388,08719
Polymers387,34315
Non-polymers7434
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 9 types, 13 molecules AEBFCGDHKNRTO

#1: Protein 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, UniProt: P84233*PLUS
#2: Protein 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 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, UniProt: P06897*PLUS
#4: Protein Histone H2B 1.1 / H2B1.1


Mass: 13498.715 Da / Num. of mol.: 2 / Mutation: S29T/K117T
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 Histone-lysine N-methyltransferase 2A / Lysine N-methyltransferase 2A / ALL-1 / CXXC-type zinc finger protein 7 / Myeloid/lymphoid or mixed- ...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
#8: Protein 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
#9: Protein 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 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
#11: Protein Ubiquitin /


Mass: 8622.922 Da / Num. of mol.: 1 / Mutation: G76C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RPS27A, UBA80, UBCEP1 / Production host: Escherichia coli (E. coli) / References: UniProt: P62979

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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

#12: Chemical ChemComp-SAH / S-ADENOSYL-L-HOMOCYSTEINE / S-Adenosyl-L-homocysteine


Type: L-peptide linking / Mass: 384.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H20N6O5S
#13: Chemical ChemComp-ZN / ZINC ION / Zinc


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


Type: L-peptide linking / Mass: 147.195 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H15N2O2
#15: Chemical ChemComp-GLN / GLUTAMINE / Glutamine


Type: L-peptide linking / Mass: 146.144 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H10N2O3

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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
IDNameTypeEntity IDParent-IDSource
1Human MLL1 complex associated with an H2B-monoubiquitinated nucleosome (3.2 angstrom)COMPLEX#1-#110MULTIPLE SOURCES
2Human MLL1KMT2ACOMPLEX#7-#111RECOMBINANT
3H2B-monoubiquitinated nucleosomeCOMPLEX#1-#61MULTIPLE SOURCES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Xenopus laevis (African clawed frog)8355
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli (E. coli)562
23Escherichia coli (E. coli)562
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: 50 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: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 139535 / Symmetry type: POINT
RefinementStereochemistry target values: GeoStd + Monomer Library
Refine LS restraints
Refinement-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.007121497
ELECTRON MICROSCOPYf_angle_d0.838630289
ELECTRON MICROSCOPYf_chiral_restr0.05233405
ELECTRON MICROSCOPYf_plane_restr0.00722832
ELECTRON MICROSCOPYf_dihedral_angle_d18.504511901

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