Special Seminar: Metalloproteinases dynamics during catalysis: application to drug design

14/11/2018 - 10:00 - 11:00

S P E C I A L  S E M I N A R


Wednesday 14/11/18, 10:00 am
Building 211, seminar room 112


SPEAKER:


Dr. Moran Grossman
Department of Physical chemistry
Ruhr University, Germany


TOPIC:


Metalloproteinases dynamics during catalysis: application to drug design


The extracellular matrix (ECM) is a complex mixture of fibrous structural proteins (such as collagen) and proteoglycans that are assembled into super-hierarchical architectures with exquisite biophysical properties. Enzymes belonging to the large family of structurally homologous metalloproteinases (MMPs) are key players in the proteolysis of ECM substrates in a wide variety of biological processes. Despite a wealth of information available on their 3D structural models and their biological functions, their detailed biophysical molecular mechanisms and the way these enzymes execute their biological activities remain elusive. In addition, models describing protein dynamics during enzymatic reactions rarely account for the individual contribution of solvent dynamics to enzyme catalysis, despite its evident importance in controlling functional motion of proteins. An advanced integrated spectroscopic approach was developed to explore the molecular interplay between metalloproteinase structural-kinetics and solvation dynamics. A combination of time resolved X-ray absorption spectroscopy with THz (Infrared) spectroscopy enabled the investigation of the role of solvation dynamics in mediating the function of membrane-type 1 MMP (MT1-MMP). The results suggested that the thousands of water molecules, that solvate the protein surface of native matrix metalloproteinase and its active site, form a steep gradient of slow to fast motions assisting substrate binding. This so called 'hydration funnel' is substrate specific, and different between structurally homologous enzymes. This suggests that changes in protein and solvent
dynamics are not mere epiphenomena, but play a vital role in the evolution of
substrate binding and recognition: they are more cause than consequence. In this
respect, the ability to monitor protein and solvation dynamics of complex protein
reactions and assemblies opens up new opportunities to study the role of water in
tissues and biogenic scaffolds in fine detail, as well as aid in the development of novel
therapeutics.

Abstract