Irit Sagi, Ph.D. |
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From molecular biophysics and structural biology to drug design: application of a multidisciplinary experimental approach to the study of metalloenzymes
The spectacular advances in the fields of protein chemistry, biology, structural biology and biophysics over the past century have now created a unique opportunity to merge these fields without regard to their borders. Our research group at the Weizmann Institute of Science employs such multidisciplinary approach to investigate molecular events governing metalloenzymes during their physiological reactions. Specifically, we pursue a multidisciplinary approach combining aspects of structural spectroscopy, single molecule imaging, reaction kinetics, biochemistry, phage display technology, and protein crystallography to study extracellular metalloenzymes (e.g. matrix metalloproteinases, MMPs) during the course of their reactions.
Along these lines, we have advanced structural dynamic approaches to investigate catalytic sites of metalloenzymes at atomic details. Our experimental approach allows the elucidation of the structure and chemistry of reactive transient species that could not be detected by conventional tools. The fine mechanistic information derived using this experimental strategy is currently used to provide insights and new leads to the design of drugs in the form of function blocking antibodies targeted at metalloenzyme catalytic sites. The therapeutic potential of these agents is explored in inflammatory and cancer disease models including Crohn's disease, multiple sclerosis, arthritis and cancer metastasis.