Membrane Protein Sciences – Tools for Rational Discovery of Novel Therapeutics and Diagnostic Targeting Integral Membrane Proteins

Integral membrane proteins (IMPs) constitute a third of prokaryotic and eukaryotic proteomes and are involved in almost every cellular process. IMP malfunction results in a range of diseases, and activity modulation of IMPs is one of the main therapeutic strategies available. The importance of IMPs in drug discovery and diagnostic applications is immense, but the knowledge of IMPs structure and mechanism is rudimentary, and technologies for in vitro studies of IMPs, which can accelerate drug design programs, are highly underdeveloped. The present proposal addresses these problems by (i) establishing a core facility for IMP production, (ii) developing innovative technologies for IMP production and stabilisation, (iii) performing mechanistic studies of IMP families of high therapeutic and diagnostic importance and (iv) developing generic strategies for in vitro selection of IMP directed ligands or binding proteins for diagnostic and therapeutic use. New library technologies for IMP production, combined with parallel platforms for screening expression parameters will be developed. These will be complemented by structure-function studies of IMPs, facilitated by new crystallisation methods of IMPs and NMR methods of structure determination specific to IMPs. Novel IMP ligand-binding paradigms will be investigated by NMR and other biophysical approaches. Another aim of this proposal is the identification of proteins that bind IMPs and the generation of specific antibodies, to be used as diagnostic or therapeutics, which will be facilitated with the availability of purified IMPs. Direct collaboration with the Novartis Tropical Institute is expected, and it is also anticipated that the funding of a leading Membrane Protein Sciences project in Singapore will attract the interest of other Pharmaceutical companies to collaborate.