PDBsum entry 2j2s

Transcription regulation

PDB id: 2j2s

Contents

Protein chain

72 a.a. *

Metals

_ZN ×2

* Residue conservation analysis

PDB id:

2j2s

Name:

Transcription regulation

Title:

Solution structure of the nonmethyl-cpg-binding cxxc domain of the leukaemia-associated mll histone methyltransferase

Structure:

Zinc finger protein hrx. Chain: a. Fragment: residues 1146-1214. Synonym: all-1, trithorax-like protein, cxxc domain of mll-1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

NMR struc:

20 models

Authors:

M.D.Allen,C.G.Grummitt,C.Hilcenko,S.Young-Min,L.M.Tonkin,C.M.Johnson, M.Bycroft,A.J.Warren

Key ref:

M.D.Allen et al. (2006). Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase. EMBO J, 25, 4503-4512. PubMed id: 16990798 DOI: 10.1038/sj.emboj.7601340

Date:

17-Aug-06 Release date: 21-Aug-06

Protein chain

Q03164  (KMT2A_HUMAN) -  Histone-lysine N-methyltransferase 2A from Homo sapiens

Seq: 3969 a.a.

Struc: 72 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.2.1.1.- - ?????
• Enzyme class 2: E.C.2.1.1.364 - [histone H3]-lysine(4) N-methyltransferase.
• Reaction: L-lysyl₄-[histone H3] + S-adenosyl-L-methionine = N₆-methyl-L- lysyl₄-[histone H3] + S-adenosyl-L-homocysteine + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1038/sj.emboj.7601340

EMBO J 25:4503-4512 (2006)

PubMed id: 16990798

Solution structure of the nonmethyl-CpG-binding CXXC domain of the leukaemia-associated MLL histone methyltransferase.

M.D.Allen, C.G.Grummitt, C.Hilcenko, S.Y.Min, L.M.Tonkin, C.M.Johnson, S.M.Freund, M.Bycroft, A.J.Warren.

ABSTRACT

Methylation of CpG dinucleotides is the major epigenetic modification of mammalian genomes, critical for regulating chromatin structure and gene activity. The mixed-lineage leukaemia (MLL) CXXC domain selectively binds nonmethyl-CpG DNA, and is required for transformation by MLL fusion proteins that commonly arise from recurrent chromosomal translocations in infant and secondary treatment-related acute leukaemias. To elucidate the molecular basis of nonmethyl-CpG DNA recognition, we determined the structure of the human MLL CXXC domain by multidimensional NMR spectroscopy. The CXXC domain has a novel fold in which two zinc ions are each coordinated tetrahedrally by four conserved cysteine ligands provided by two CGXCXXC motifs and two distal cysteine residues. We have identified the CXXC domain DNA binding interface by means of chemical shift perturbation analysis, cross-saturation transfer and site-directed mutagenesis. In particular, we have shown that residues in an extended surface loop are in close contact with the DNA. These data provide a template for the design of specifically targeted therapeutics for poor prognosis MLL-associated leukaemias.

Selected figure(s)

Figure 1.
Figure 1 Solution structure of the MLL CXXC domain. (A) An overlay of the backbone atoms of the 20 lowest energy structures in stereo. (B) A ribbon representation of the lowest energy structure (same orientation as in (A)), prepared using the program PyMOL (http://www.pymol.org). Zn ions are shown as spheres. (C) A ribbon representation of the Zn coordination sites in MLL (PyMOL).

Figure 2.
Figure 2 Ribbon representation of the elaborate turn in the CXXC domain of MLL showing the side chains of the residues from the KFGG motif and the second Zn coordination site (PyMOL). An extended loop is formed between residues G1181 and C1189.

The above figures are reprinted by permission from Macmillan Publishers Ltd: EMBO J (2006, 25, 4503-4512) copyright 2006.

Figures were selected by the author.