Advances in NMR Methods to Identify Allosteric Sites and Allosteric Ligands.

NMR allows assessment of protein structure in solution. Unlike conventional X-ray crystallography that provides snapshots of protein conformations, all conformational states are simultaneously accessible to analysis by NMR. This is a significant advantage for discovery and characterization of allosteric effects. These effects are observed when binding at one site of the protein affects another distinct site through conformational transitions. Allosteric regulation of proteins has been observed in multiple physiological processes in health and disease, providing an opportunity for the development of allosteric inhibitors. These compounds do not directly interact with the orthosteric site of the protein but influence its structure and function. In this book chapter, we provide an overview on how NMR methods are utilized to identify allosteric sites and to discover novel inhibitors, highlighting examples from the field. We also describe how NMR has contributed to understanding of allosteric mechanisms and propose that it is likely to play an important role in clarification and further development of key concepts of allostery.