Replicating a Complex Natural Event Using a Simple Synthetic Host
Brandin Lilgert, Cory Beshera, and Fraser Hof*
Department of Chemistry, University of Victoria, Victoria, BC, Canada
Studies have confirmed that the tri-methylation of lysine 9 (K9) on histone 3 (H3)
invokes a binding event with heterochromatin protein 1 (HP1).1 The receptor site
(chromodomain) on HP1 is comprised of highly aromatic residues which have a high
affinity for tri-methylated lysine through cation-pi interactions.2 It has also been shown
that by phosphorylating the neighbouring serine 10 (S10) on H3, binding between H3
and HP1 can be “turned off” in the manner of a binary switch.1
Using p-sulfonatocalix[4]arene (PSC4) as a chromodomain mimic, the binding
strength between non-methylated lysine was compared to that with varying degrees of
methylation using 1H nmr titrations in a phosphate buffer solution at pH=7.4. As
previously shown,3 by methylating a lysine residue the binding strength increases x100
M-1 when compared to that of the unmodified lysine. Now that we have confirmed this
titration method, and the results have been shown to be reproducible, a similar
investigation is to be done using the peptide Arg-Lys-Ser-Thr (RKST). By measuring the
binding strength between lysine in RKST and PSC4 we will replicate the binary
switching event through modifications of the lysine and serine residues. Replicating this
natural event will provide some insight into the driving force behind the binary switch
seen between H3 and HP1.
References:
1. Fischle, W.; Tseng, B. S. Nature 2005, 438, 1116-1122.
2. Ma, J. C.; Dougherty, D. A. Chem. Rev. 1997, 97, 1303-1324.
3. Douteau-Guevel, N.; Coleman, A. W. J. Chem. Soc. 1999, 97, 629-633.