The Baird Lab

Manipulating proteases, so you don't have to.

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We are a biochemistry lab in the Chemistry and Biochemistry Department at San Francisco State University. Our research interests are in protein structure-function relationships, particularly substrate specificity, catalysis and inhibition in serine proteases. I have little doubt that you've heard of the serine protease trypsin. It's in every biochemistry text book, it's used in mass spectroscopy studies and it's been studied for over 50 years. Well, in the Baird Lab, we use trypsin as a model system because its scaffold is representative of a number of other serine proteases making our results potentially applicable to more than 100 other enzymes. Because there is so much already known about it, it an excellent system for protein engineering experiments in this family of enzymes and it is relatively easy to mutagenize, express, purify and characterize.

Catalysis and Substrate Selectivity
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One of the basic science questions we asked was, why do we not observe many threonine proteases in nature? Using molecular modeling, we hypothesized that structural limitations imposed by the presence of a disulfide bridge near the active site precluded the use of the chemically similar, but larger threonine at position 195. Consequently, we hypothesized that we could remove this disulfide bridge which should allow for threonine to be used similarly to serine in the catalytic mechanism. We were successful in creating a functional threonine protease within the trypsin scaffold. Recently, in collaboration with the Guliaev Lab at SFSU, we carried out computational studies that support the original hypothesis. We are also investigating how these structural changes lead to changes in substrate selectivity.

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Proteases are involved in nearly every biological process in some way. Consequently, they have long been targets of small molecule drugs. However, more recently, proteases (particularly trypsin-fold proteases) are now being developed to be used as drugs themselves. One of the inherent difficulties is the presence of naturally occurring inhibitors that exist to prevent unnecessary or errant proteolysis. Once a proteolytic drug is delivered, its lifetime is relatively short because of such protective measures. Our lab is using protein engineering approaches to identify sites that are important for protease-inhibitor association with the intent of weakening these interactions without eliminating or reducing catalytic activity significantly.