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

最近，我们已经使用NMR、X射线晶体学和酵母表面展示来工程化基于来自胰岛素生长因子2受体（IGF 2 R）的结构域11的IGF 2超级拮抗剂（Crump &哈桑and co-workers 2012，Science 238，1209-1213.）。这种300 kDa蛋白质含有15个结构同源的β-桶结构域（~ 140 aa），其存在4个高变表面环，其结合各种大小的配体，从甘露糖-6-磷酸单酯、Man-P-GlcNAc磷酸二酯（不同的结构域区分单酯和二酯）、视黄酸直至较大的蛋白质，如胰岛素生长因子-2。这种多样性是前所未有的，揭示了这种底层支架的复杂性以及在生物技术和生物应用中的潜力。我们的目标是继续设计IGF 2 R的结构域，包括结构域9、11和7，以探索它们的小分子（例如凝集素结合特性）和对IGF 2不同亚型的亲和力，以期设计选择性陷阱。

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.