Picking pockets

By now you have probably noticed that I have a lot of respect for cool publication titles. Earlier today I was thinking about some of the great ones. Who can beat Barry Sharpless’s “Vicinal Diol Cyclic Sulfates – Like Epoxides Only More Reactive”? I just love it. You can find this paper on the link below:

http://pubs.acs.org/doi/pdf/10.1021/ja00230a045.

Here is another one. It is a paper that comes “close to home” from the standpoint of our projects that are directed towards fragment-based interrogation of epigenetic proteins: “How Chromatin-binding Modules Interpret Histone Modifications: Lessons From Professional Pocket-Pickers”:

http://www.nature.com/nsmb/journal/v14/n11/abs/nsmb1338.html.

This manuscript details some of the intricate ways used by histone binding domains to differentiate among mono-, bis-, and trimethyllysine (to name a few) residues within histone proteins. Biologists might not yet know the rules that govern this complex process, but they are trying to find out. Chemists are uniquely suited to play an important role in this process by finding molecules that can disrupt the corresponding protein-protein interactions. To do this, we need two components: a well behaved domain that recognizes a post-translationally modified amino acid of interest and a method of making small molecules that disrupt this interaction with high specificity. Ever since I ended my sabbatical stay at the SGC in December of 2013, my graduate student Victoria (shown below) took over the reins and delved into various ways to produce and crystallographically characterize methyllysine-binding targets in collaboration with the SGC. Elena (shown below) has been her mentor in this undertaking. Last night Victoria made an important step forward: one of the key trimethyllysine-binding proteins succumbed to crystallographic characterization. Victoria was able to isolate and crystallize the molecule which is shown below on the right hand side (I made the images using PyMol). SGC’s Aiping Dong has been instrumental (as always) in solving the structure. You see two proteins side by side. On the left is the trimethyllysine containing peptide bound to the target, and on the right is Victoria’s domain that contains an empty pocket. Which molecules can get in and stay there? This is for Victoria to find out… We need to understand how these “professional pocket pickers” work.

Image

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