PDBsum entry 4esg

Transcription/transferase

PDB id: 4esg

Contents

Protein chains

304 a.a.

16 a.a.

Waters ×627

PDB id:

4esg

Name:

Transcription/transferase

Title:

X-ray structure of wdr5-mll1 win motif peptide binary complex

Structure:

Wd repeat-containing protein 5. Chain: a, b. Fragment: unp residues 23-334. Synonym: bmp2-induced 3-kb gene protein. Engineered: yes. Histone-lysine n-methyltransferase mll. Chain: c, d. Fragment: unp residues 3755-3771. Synonym: all-1, cxxc-type zinc finger protein 7, lysine n-

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: big3, wdr5. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606

Resolution:

1.70Å R-factor: 0.164 R-free: 0.193

Authors:

V.Dharmarajan,J.-H.Lee,A.Patel,D.G.Skalnik,M.S.Cosgrove

Key ref:

V.Dharmarajan et al. (2012). Structural basis for WDR5 interaction (Win) motif recognition in human SET1 family histone methyltransferases. J Biol Chem, 287, 27275-27289. PubMed id: 22665483

Date:

23-Apr-12 Release date: 30-May-12

Protein chains

P61964  (WDR5_HUMAN) -  WD repeat-containing protein 5 from Homo sapiens

Seq: 334 a.a.

Struc: 304 a.a.

Protein chains

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

Seq: 3969 a.a.

Struc: 16 a.a.

Enzyme reactions

• Enzyme class 1: Chains C, D: E.C.2.1.1.- - ?????
• Enzyme class 2: Chains C, D: 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

J Biol Chem 287:27275-27289 (2012)

PubMed id: 22665483

Structural basis for WDR5 interaction (Win) motif recognition in human SET1 family histone methyltransferases.

V.Dharmarajan, J.H.Lee, A.Patel, D.G.Skalnik, M.S.Cosgrove.

ABSTRACT

Translocations and amplifications of the mixed lineage leukemia-1 (MLL1) gene are associated with aggressive myeloid and lymphocytic leukemias in humans. MLL1 is a member of the SET1 family of histone H3 lysine 4 (H3K4) methyltransferases, which are required for transcription of genes involved in hematopoiesis and development. MLL1 associates with a subcomplex containing WDR5, RbBP5, Ash2L, and DPY-30 (WRAD), which together form the MLL1 core complex that is required for sequential mono- and dimethylation of H3K4. We previously demonstrated that WDR5 binds the conserved WDR5 interaction (Win) motif of MLL1 in vitro, an interaction that is required for the H3K4 dimethylation activity of the MLL1 core complex. In this investigation, we demonstrate that arginine 3765 of the MLL1 Win motif is required to co-immunoprecipitate WRAD from mammalian cells, suggesting that the WDR5-Win motif interaction is important for the assembly of the MLL1 core complex in vivo. We also demonstrate that peptides that mimic SET1 family Win motif sequences inhibit H3K4 dimethylation by the MLL1 core complex with varying degrees of efficiency. To understand the structural basis for these differences, we determined structures of WDR5 bound to six different naturally occurring Win motif sequences at resolutions ranging from 1.9 to 1.2 Å. Our results reveal that binding energy differences result from interactions between non-conserved residues C-terminal to the Win motif and to a lesser extent from subtle variation of residues within the Win motif. These results highlight a new class of methylation inhibitors that may be useful for the treatment of MLL1-related malignancies.