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- PDB-6pwv: Cryo-EM structure of MLL1 core complex bound to the nucleosome -

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Entry
Database: PDB / ID: 6pwv
TitleCryo-EM structure of MLL1 core complex bound to the nucleosome
Components
  • (DNA (147-MER)) x 2
  • Histone H2A type 1
  • Histone H2B 1.1
  • Histone H3.2
  • Histone H4
  • Histone-lysine N-methyltransferase 2A
  • Protein dpy-30 homolog
  • Retinoblastoma-binding protein 5
  • Set1/Ash2 histone methyltransferase complex subunit ASH2
  • WD repeat-containing protein 5
KeywordsHISTONE BINDING/DNA BINDING/DNA / Mixed-Lineage Leukemia / MLL1 / nucleosome / histone H3 Lys4 methyltransferase / RbBP5 / WDR5 / HISTONE BINDING-DNA BINDING-DNA complex
Function / homology
Function and homology information


protein-cysteine methyltransferase activity / response to potassium ion / [histone H3]-lysine4 N-methyltransferase / histone H3K4 monomethyltransferase activity / unmethylated CpG binding / histone H3K4 trimethyltransferase activity / negative regulation of DNA methylation-dependent heterochromatin formation / regulation of short-term neuronal synaptic plasticity / MLL3/4 complex / Set1C/COMPASS complex ...protein-cysteine methyltransferase activity / response to potassium ion / [histone H3]-lysine4 N-methyltransferase / histone H3K4 monomethyltransferase activity / unmethylated CpG binding / histone H3K4 trimethyltransferase activity / negative regulation of DNA methylation-dependent heterochromatin formation / regulation of short-term neuronal synaptic plasticity / MLL3/4 complex / Set1C/COMPASS complex / MLL1/2 complex / ATAC complex / definitive hemopoiesis / NSL complex / histone H3K4 methyltransferase activity / T-helper 2 cell differentiation / : / Cardiogenesis / embryonic hemopoiesis / exploration behavior / anterior/posterior pattern specification / endosomal transport / histone methyltransferase complex / regulation of tubulin deacetylation / : / regulation of cell division / Formation of WDR5-containing histone-modifying complexes / minor groove of adenine-thymine-rich DNA binding / membrane depolarization / MLL1 complex / regulation of embryonic development / hemopoiesis / histone acetyltransferase complex / negative regulation of fibroblast proliferation / homeostasis of number of cells within a tissue / positive regulation of gluconeogenesis / spleen development / transcription initiation-coupled chromatin remodeling / cellular response to transforming growth factor beta stimulus / methylated histone binding / Transferases; Transferring one-carbon groups; Methyltransferases / post-embryonic development / skeletal system development / Deactivation of the beta-catenin transactivating complex / gluconeogenesis / Formation of the beta-catenin:TCF transactivating complex / circadian regulation of gene expression / protein modification process / lysine-acetylated histone binding / euchromatin / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / visual learning / trans-Golgi network / mitotic spindle / PKMTs methylate histone lysines / RMTs methylate histone arginines / beta-catenin binding / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Transcriptional regulation of granulopoiesis / structural constituent of chromatin / response to estrogen / nucleosome / Neddylation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / HATs acetylate histones / histone binding / fibroblast proliferation / protein-containing complex assembly / transcription cis-regulatory region binding / regulation of cell cycle / protein heterodimerization activity / apoptotic process / DNA damage response / chromatin binding / positive regulation of cell population proliferation / nucleolus / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / Golgi apparatus / negative regulation of transcription by RNA polymerase II / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / identical protein binding / metal ion binding / nucleus / cytosol
Similarity search - Function
Sdc1/DPY30 / Dpy-30 motif / Dpy-30 motif / ASH2, PHD zinc finger / Set1/Ash2 histone methyltransferase complex subunit ASH2-like, WH / Histone methyltransferase complex subunit ASH2 / Retinoblastoma-binding protein 5/Swd1 / KMT2A, ePHD domain / KMT2A, PHD domain 1 / KMT2A, PHD domain 2 ...Sdc1/DPY30 / Dpy-30 motif / Dpy-30 motif / ASH2, PHD zinc finger / Set1/Ash2 histone methyltransferase complex subunit ASH2-like, WH / Histone methyltransferase complex subunit ASH2 / Retinoblastoma-binding protein 5/Swd1 / 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. / SPRY domain / B30.2/SPRY domain / B30.2/SPRY domain profile. / SPRY domain / B30.2/SPRY domain superfamily / Domain in SPla and the RYanodine Receptor. / SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain / SET domain superfamily / SET domain / SET domain profile. / SET domain / Extended PHD (ePHD) domain / Extended PHD (ePHD) domain profile. / PHD-finger / Zinc finger PHD-type signature. / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site / Histone H2A signature. / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone H2A / Histone 2A / Histone H4, conserved site / Histone H4 signature. / Histone H4 / Histone H4 / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / Zinc finger PHD-type profile. / Zinc finger, PHD-finger / Histone H3 signature 1. / Zinc finger, PHD-type / PHD zinc finger / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Zinc finger, FYVE/PHD-type / Histone-fold / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Concanavalin A-like lectin/glucanase domain superfamily / G-protein beta WD-40 repeat / Zinc finger, RING/FYVE/PHD-type / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
S-ADENOSYL-L-HOMOCYSTEINE / DNA / DNA (> 10) / DNA (> 100) / Histone H2B 1.1 / Histone H2A type 1 / WD repeat-containing protein 5 / Histone H4 / Histone H3.2 / Histone-lysine N-methyltransferase 2A ...S-ADENOSYL-L-HOMOCYSTEINE / DNA / DNA (> 10) / DNA (> 100) / Histone H2B 1.1 / Histone H2A type 1 / WD repeat-containing protein 5 / Histone H4 / Histone H3.2 / Histone-lysine N-methyltransferase 2A / Retinoblastoma-binding protein 5 / Protein dpy-30 homolog / Set1/Ash2 histone methyltransferase complex subunit ASH2
Similarity search - Component
Biological speciesHomo sapiens (human)
Xenopus laevis (African clawed frog)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.2 Å
AuthorsPark, S.H. / Ayoub, A. / Lee, Y.T. / Xu, J. / Zhang, W. / Zhang, B. / Zhang, Y. / Cianfrocco, M.A. / Su, M. / Dou, Y. / Cho, U.
Funding support United States, Korea, Republic Of, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Center for Research Resources (NIH/NCRR)DK111465 United States
National Research Foundation (NRF, Korea)NRF-2015M3D3A1A01064876 Korea, Republic Of
CitationJournal: Nat Commun / Year: 2019
Title: Cryo-EM structure of the human MLL1 core complex bound to the nucleosome.
Authors: Sang Ho Park / Alex Ayoub / Young-Tae Lee / Jing Xu / Hanseong Kim / Wei Zheng / Biao Zhang / Liang Sha / Sojin An / Yang Zhang / Michael A Cianfrocco / Min Su / Yali Dou / Uhn-Soo Cho /
Abstract: Mixed lineage leukemia (MLL) family histone methyltransferases are enzymes that deposit histone H3 Lys4 (K4) mono-/di-/tri-methylation and regulate gene expression in mammals. Despite extensive ...Mixed lineage leukemia (MLL) family histone methyltransferases are enzymes that deposit histone H3 Lys4 (K4) mono-/di-/tri-methylation and regulate gene expression in mammals. Despite extensive structural and biochemical studies, the molecular mechanisms whereby the MLL complexes recognize histone H3K4 within nucleosome core particles (NCPs) remain unclear. Here we report the single-particle cryo-electron microscopy (cryo-EM) structure of the NCP-bound human MLL1 core complex. We show that the MLL1 core complex anchors to the NCP via the conserved RbBP5 and ASH2L, which interact extensively with nucleosomal DNA and the surface close to the N-terminal tail of histone H4. Concurrent interactions of RbBP5 and ASH2L with the NCP uniquely align the catalytic MLL1 domain at the nucleosome dyad, thereby facilitating symmetrical access to both H3K4 substrates within the NCP. Our study sheds light on how the MLL1 complex engages chromatin and how chromatin binding promotes MLL1 tri-methylation activity.
History
DepositionJul 23, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 18, 2020Group: Structure summary / Category: struct / Item: _struct.title
Revision 1.2Aug 16, 2023Group: Data collection / Database references / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.pdb_format_compatible

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Structure visualization

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Assembly

Deposited unit
A: Retinoblastoma-binding protein 5
B: WD repeat-containing protein 5
C: Histone-lysine N-methyltransferase 2A
G: Histone H3.2
H: Histone H4
I: Histone H2A type 1
J: Histone H2B 1.1
K: Histone H3.2
L: Histone H4
M: Histone H2A type 1
N: Histone H2B 1.1
O: DNA (147-MER)
P: DNA (147-MER)
E: Protein dpy-30 homolog
F: Protein dpy-30 homolog
D: Set1/Ash2 histone methyltransferase complex subunit ASH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)401,25620
Polymers400,35616
Non-polymers9004
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 9 types, 14 molecules ABCGKHLIMJNEFD

#1: Protein Retinoblastoma-binding protein 5 / RBBP-5 / Retinoblastoma-binding protein RBQ-3


Mass: 59179.359 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
#2: Protein WD repeat-containing protein 5 / BMP2-induced 3-kb gene protein


Mass: 34390.992 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
#3: 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: 24141.732 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
#4: Protein Histone H3.2 / Histone H3


Mass: 15435.126 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: P84233
#5: Protein Histone H4 /


Mass: 11394.426 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
#6: Protein Histone H2A type 1


Mass: 13978.241 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: P06897
#7: Protein Histone H2B 1.1 / H2B1.1


Mass: 13524.752 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: P02281
#10: Protein Protein dpy-30 homolog / Dpy-30-like protein / Dpy-30L


Mass: 11492.876 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DPY30 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9C005
#11: Protein Set1/Ash2 histone methyltransferase complex subunit ASH2 / ASH2-like protein


Mass: 60244.641 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 OP

#8: DNA chain DNA (147-MER)


Mass: 45138.770 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#9: DNA chain DNA (147-MER)


Mass: 45610.043 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 2 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.: 2 / Source method: obtained synthetically / Formula: C14H20N6O5S / Feature type: SUBJECT OF INVESTIGATION
#13: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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

ComponentName: Human MLL1 complex bound to the nucleosome / Type: COMPLEX / Entity ID: #1-#11 / Source: MULTIPLE SOURCES
Source (natural)Organism: Xenopus laevis (African clawed frog)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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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: OTHER
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 64 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 6.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 8433 / Symmetry type: POINT

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