title: Structural study of a small molecule receptor bound to dimethyllysine in lysozyme.
abstract: Lysine is a ubiquitous residue on protein surfaces. Post translational modifications of lysine, including methylation to the mono-, di- or trimethylated amine result in chemical and structural alterations that have major consequences for protein interactions and signalling pathways. Small molecules that bind to methylated lysines are potential tools to modify such pathways. To make progress in this direction, detailed structural data of ligands in complex with methylated lysine is required. Here, we report a crystal structure ofp-sulfonatocalix[4]arene (sclx4) bound to methylated lysozyme in which the lysine residues were chemically modified from Lys-NH3+to Lys-NH(Me2)+. Of the six possible dimethyllysine sites, sclx4selected Lys116-Me2and the dimethylamino substituent was deeply buried in the calixarene cavity. This complex confirms the tendency for Lys-Me2residues to form cation-π interactions, which have been shown to be important in protein recognition of histone tails bearing methylated lysines. Supporting data from NMR spectroscopy and MD simulations confirm the selectivity for Lys116-Me2in solution. The structure presented here may serve as a stepping stone to the development of new biochemical reagents that target methylated lysines.
authors.affiliation: School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland.
authors.forename: Róise E
authors.initials: RE
authors.lastname: McGovern
authors.affiliation: Department of Chemistry, University of Victoria, British Columbia, V8W 3V6, Canada.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Snarr
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Lyons
authors.affiliation: Department of Chemistry, University of Victoria, British Columbia, V8W 3V6, Canada.
authors.forename: James
authors.initials: J
authors.lastname: McFarlane
authors.affiliation: Department of Chemistry, University of Victoria, British Columbia, V8W 3V6, Canada.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Whiting
authors.affiliation: Department of Chemistry, University of Victoria, British Columbia, V8W 3V6, Canada.
authors.forename: Irina
authors.initials: I
authors.lastname: Paci
authors.affiliation: Department of Chemistry, University of Victoria, British Columbia, V8W 3V6, Canada.
authors.forename: Fraser
authors.initials: F
authors.lastname: Hof
authors.affiliation: School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Crowley
keywords: Dimethyl lysine; Methylation; Protein interactions; Synthetic receptor