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Protein exosites, cryptic sites and moonlighting: identification, functional mapping and effects of changes in structure

Abstract

The interior of organisms constitute complex, crowded and dynamic environments with little semblance to the experiments conducted on isolated proteins. Data on the possible interactions that specific proteins can participate in within these crowded physiological environments is fundamental to understanding the multiple roles that are frequently played by proteins. High-resolution structural data have been instrumental in characterizing and defining the stereochemical parameters that promote and define the binding of peptides, protein inhibitors and substrates at the active sites of enzymes to the point that we now have a very comprehensive understanding of specific interactions and catalytic mechanisms which facilitate the design and development of highly selective synthetic inhibitors and drugs. On a more subtle level, protein surfaces often bristle with secondary binding sites (exosites), which serve key roles in regulating and modulating diverse activities ranging from gene expression, conformational stabilization, transport, inhibition and, by extension, the modulation and exhibition of distinct functions or moonlighting by the same enzyme in response to changes in physicochemical conditions are less well understood. This proposal combines high-throughput/high-resolution techniques such as phage display, metabolomics, structural biology, computational biology, along with fragment based computational methods to map, select and evaluate protein surfaces and cryptic sites that specifically interact with peptides and proteins and to identify the underlying dynamic protein-protein interactions that occur under different physiological conditions. The core of this proposal is centred on proteins of biological relevance that are currently being studied in our research group to understand their interactions with peptides and with other proteins to discern their possible multiple roles. The scientists participating in this research proposal have maintained an intensive exchange program and been successfully collaborating over a long period as evidenced by the joint publications and patent applications. (AU)

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