PDBsum entry 2h6k

Gene regulation

PDB id

2h6k

Contents

			Protein chains

					305 a.a.

			Ligands

					ALA-ARG-THR-MLZ- GLN-THR-ALA-ARG- LYS


					ALA-ARG-THR-MLZ- GLN-THR-ALA-ARG

			Waters ×696

References listed in PDB file

Key reference

Title

Histone h3 recognition and presentation by the wdr5 module of the mll1 complex.

Authors

A.J.Ruthenburg, W.Wang, D.M.Graybosch, H.Li, C.D.Allis, D.J.Patel, G.L.Verdine.

Ref.

Nat Struct Mol Biol, 2006, 13, 704-712. [DOI no: 10.1038/nsmb1119]

PubMed id

16829959

Abstract

WDR5 is a core component of SET1-family complexes that achieve transcriptional activation via methylation of histone H3 on Nzeta of Lys4 (H3K4). The role of WDR5 in the MLL1 complex has recently been described as specific recognition of dimethyl-K4 in the context of a histone H3 amino terminus; WDR5 is essential for vertebrate development, Hox gene activation and global H3K4 trimethylation. We report the high-resolution X-ray structures of WDR5 in the unliganded form and complexed with histone H3 peptides having unmodified and mono-, di- and trimethylated K4, which together provide the first comprehensive analysis of methylated histone recognition by the ubiquitous WD40-repeat fold. Contrary to predictions, the structures reveal that WDR5 does not read out the methylation state of K4 directly, but instead serves to present the K4 side chain for further methylation by SET1-family complexes.



	Figure 3. Figure 3. Peptide recognition by WDR5 and conformational changes upon peptide binding. (a) The peptide is recognized by an elaborate series of direct and indirect contacts. Orientation of the peptide–WDR5 complex is the same as in the lower panel of Figure 1c. The majority of direct contacts from WDR5 are made to the N terminus and the first three residues. These residues adopt an approximately helical main chain conformation, with one hydrogen bond between the A1 and K4 backbone. Water-mediated contacts are important in recognition of the C-terminal residues of the peptide, as all waters shown (red spheres) are conserved among the peptide-bound structures. Tyr191 apparently acts as a central platform in this peptide-bound water network. (b) Phe133 and Phe263 form an aromatic sandwich about the R2 guanidinium moiety, equatorially flanked by a number of backbone carbonyl–mediated hydrogen bonds. These tight hydrogen bonds are thought to impart specificity for arginine over dimethyllysine, particularly the one from N of R2 to the Ser91 carbonyl. (c) Apparent coordinated movement of Phe133 and Phe149 to form the top of the aromatic sandwich recognition element when peptide is bound. The relevant apostructure side chains are depicted in gray and a representative liganded structure (H3K4me2 complex I) is in crimson. (d) Retraction of the loop bearing Lys259 causes a reorganization of the residues lining the central cavity, which permits tight R2 coordination. Coloring is as in c. This movement may be driven by a steric clash between this lysine and the incoming peptide Q5 side chain.		Figure 5. Figure 5. Differences in K4 conformation in the different methylation states. (a–d) The crystal-packing interface relevant to K4 conformation is depicted for the H3K4me3 complex (C2 space group, a), H3K4me2 complex I (C2, b), H3K4me1 complex (C2, c) and unmodified H3 complex (P2[1], d). Peptides are colored as in Figure 2b; the principal WDR5 protomer is red; and the symmetry-related protomer at the peptide interface is gray. Note the rotation about 3 moving from the tri- and dimethylated species to the monomethylated and unmodified species. In H3K4me2 complex I, the distances between the -methyl carbons and the Glu322 carboxylate O 1 are 3.27 Å and 3.37 Å for the closest methyl group in each of the two complexes per asymmetric unit, whereas these distances are 3.83 Å and 3.87 Å for the more distant methyl group. For comparison, the previously reported shorter distances for these measurements were 3.15 Å and 3.42 Å^22.

PROCHECK

	Headers