Structural characterisation of a carbohydrate binding domain of the human cation-independent mannose 6-phosphate/ IGF2 receptor.

Recently we have used NMR, X-ray crystallography and yeast surface display to engineer an IGF2 super-antagonist based on domain 11 from the insulin growth factor 2 receptor (IGF2R) (Crump & Hassan and co-workers 2012, Science 238, 1209-1213.). This 300 kDa protein contains fifteen structurally homologous, Beta-barrel domains (~140aa) that present four hyper-variable surface loops that bind a variety of ligands ranging in size from mannose-6-phosphate monoesters, Man-P-GlcNAc phosphodiesters (different domains differentiate mono- and di-esters), retinoic acid, up to larger proteins such as Insulin Growth Factor-2. This diversity is unprecedented and reveals the sophistication of this underlying scaffold and the potential for use in biotechnology and biological applications. Our aim is to continue to engineer domains of IGF2R, including domain 9, 11 and 7,to explore both their small molecule (eg lectin binding properties) and affinities for different iso-forms of IGF2 with a view to engineering selective traps.