Tissue remodeling - from biophysical principles to drug design:
A multidisciplinary approach to study the extra-cellular matrix
Spectacular advances in protein chemistry, structural biology and molecular biophysics of the past century allowed us to merge these fields regardless of their borders. We established such multidisciplinary approach to investigate molecular events governing metalloenzymes during their physiological reactions. Specifically, we combine aspects of structural spectroscopy, single molecule imaging, reaction kinetics, biochemistry, phage display technology and protein crystallography to study extracellular metalloenzymes like matrix metalloproteinases (MMPs) upon their reactions.
Utilizing our novel strategy, we investigated structural dynamics at catalytic sites of metalloenzymes in real-time and at atomic detail. Our experimental approach allows the structural and chemical analysis of reaction intermediates which could not be detected otherwise. The mechanistic detail derived from our experimental strategy provides insight and innovation, leading to drug design in the form of function-blocking antibodies targeting the catalytic site of metalloenzymes. We explore the therapeutic potential of these agents in auto-immune and cancer disease models including Crohn's disease, multiple sclerosis, arthritis and cancer metastasis.