Soakers

Below is the structure of Fxr1. It is a methyl lysine-binding domain of human mental retardation-related protein 1, which is an important target. While I was in Russia (back as of yesterday), Elena emailed me with the good news that we now have Fxr1 crystals. We need them for co-crystallization/soaking experiments. Unfortunately, the quality of these crystals is not high and we have to continue our efforts to optimize these crystals. I hope this is something my graduate student Victoria will be able to do at some point…

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Right now I want to make a distinction between co-crystallization and soaking of crystals. Co-crystallization is when we attempt to crystallize a protein along with its small molecule binder. If anything, this can actually help us in the case of Fxr1 (above) as there is a chance that the molecules we designed will improve the crystal quality. On the other hand, soaking is when you already have good quality protein crystals and place them into a solution of a small molecule. The idea is that a small molecule diffuses into the lattice and “gets stuck” in places that are not random. This is a blueprint for the discovery of new probes for proteins that have no cognate ligands.

Tomorrow is the day when I am going to “cross the Rubicon”: we intend to run soaking experiments together with Dr. Aman Iqbal. Aman is an expert in soaking, having arrived to SGC from Astex in Boston. Recently, Aman managed to get a co-crystal for one of our joint targets. Tomorrow is the time to soak another one of our target proteins in cocktails of small molecules. We intend to produce around 80 crystals and analyze them by X-ray crystallography to find binders. While I was away in Russia, Conor, Rebecca and Shinya worked hard and made a library of structurally advanced fragments. In addition, we got some really cool compounds from Prof. Laurel Schafer (UBC) and her Ph.D. student, Andrey Borzenko (by FedEx earlier today). I hope we will collaborate with more people who have nice heterocycles and are keen to understand how they interact with complex protein targets. I am particularly hoping to have something interesting going with Laurel’s nice molecules. I will blog about her methods at some point. I think it is fair to say that our heterocycle-related methodology these days It is geared towards filling the holes on protein surfaces. This is fun.

At the end, I just can’t help but recall that nice paper by Fujita in Nature (http://www.nature.com/nature/journal/v495/n7442/full/nature11990.html). In it, he describes what is effectively an inorganic analog of the 3D protein lattice/small molecule soaking experiment. The paper is awesome, but I just caught myself thinking that a version of this method has been among protein scientists’ tricks for a while. I refer to soaking, of course…

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