Structural study of a small molecule receptor bound to dimethyllysine in lysozyme
| dc.contributor.author | McGovern, Roise E. | |
| dc.contributor.author | Snarr, Brendan D. | |
| dc.contributor.author | Lyons, Joseph A. | |
| dc.contributor.author | McFarlane, James | |
| dc.contributor.author | Whiting, Amanda L. | |
| dc.contributor.author | Paci, Irina | |
| dc.contributor.author | Hof, Fraser | |
| dc.contributor.author | Crowley, Peter B. | |
| dc.date.accessioned | 2020-11-13T19:55:01Z | |
| dc.date.available | 2020-11-13T19:55:01Z | |
| dc.date.copyright | 2015 | en_US |
| dc.date.issued | 2015 | |
| dc.description.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 of p-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, sclx4 selected Lys116-Me2 and the dimethylamino substituent was deeply buried in the calixarene cavity. This complex confirms the tendency for Lys-Me2 residues 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-Me2 in solution. The structure presented here may serve as a stepping stone to the development of new biochemical reagents that target methylated lysines. | en_US |
| dc.description.reviewstatus | Reviewed | en_US |
| dc.description.scholarlevel | Faculty | en_US |
| dc.description.sponsorship | This research was supported by NUI Galway (college scholarship to REM, Millennium Fund to PBC), NSERC grants to IP and FH (Canada Research Chair), and Science Foundation Ireland (10/ RFP/BIC2807 to PBC). JAL was funded by grants 07/IN.1/B1836 (SFI) and GM75915 (NIH) to M. Caffrey. ALW was funded by a Michael Smith Foundation for Health Research fellowship. We acknowledge the Swiss light source and the European synchrotron radiation facility for beam time allocation, and the staff of beam lines X10SA (Villigen) and BM14 (Grenoble) for assistance with data collection. Computational work was performed using WestGrid, funded in part by the Canada Foundation for Innovation, Alberta Innovation and Science, BC Advanced Education, and the participating research institutions. For their assistance we thank colleagues at TCD; V. Pye, A. R. Khan, and UVic; M. Beatty, L. Netter, C. Bohne, C. Greenwood, C. Barr, O. Granot. | en_US |
| dc.identifier.citation | McGovern, R. E., Snarr, B. D., Lyons, J. A., McFarlane, J., Whiting, A. L., Paci, I., … Crowley, P. B. (2015). Structural study of a small molecule receptor bound to dimethyllysine in lysozyme. Chemical Science, 6(1). https://doi.org/10.1039/c4sc02383h | en_US |
| dc.identifier.uri | https://doi.org/10.1039/c4sc02383h | |
| dc.identifier.uri | http://hdl.handle.net/1828/12349 | |
| dc.language.iso | en | en_US |
| dc.publisher | Chemical Science | en_US |
| dc.subject.department | Department of Chemistry | |
| dc.title | Structural study of a small molecule receptor bound to dimethyllysine in lysozyme | en_US |
| dc.type | Article | en_US |