Characterising the dynamics of movement and mechanism in medically relevant molecular machines (MACMILLAN_U17ICASE)

We study the architecture and functional dynamics of membrane proteins, many medically relevant. Special interest is on large multi-subunit complexes such as transporter systems and their interaction with intra-cellular signalling pathways. There is increasing evidence that membrane proteins do not act alone, but that they are organised as nano-machineries which function through the concerted action of individual components with high precision and specificity observed in both time and space. We are seeking to unravel the principles underlying the architecture and dynamics of these protein nano-machineries as well as their function and regulation. Our experimental approach focuses on the use of magnetic resonance spectroscopies in combination with novel encapsulation techniques to enhance protein yield thus allowing unambiguous experimental observations to provide a dynamic description of function. This project addresses the important theme of transport across biological membrane through the study of amino acid transporters LeuT and GltPh which are members of the SLC6 and SLC1 transporter families, both structural homologues of key human transporters implicated in several diseased states including depression, anxiety and attention-deficit hyperactivity disorder. Recent static crystal structures have suggested large scale conformational changes and we aim to probe the functional dynamics of the protein using state-of-the-art magnetic resonance techniques and novel protein encapsulation methods.