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

最近，我们利用核磁共振、x射线晶体学和酵母表面显示技术，设计了一种基于胰岛素生长因子2受体（IGF2R）结构域11的IGF2超级拮抗剂（Crump & Hassan和同事2012，Science 238, 1209-1213）。这个300 kDa的蛋白含有15个结构同源的β -桶结构域（~140aa），它们呈现4个超可变的表面环，结合各种配体，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，到更大的蛋白质，如胰岛素生长因子-2。这种多样性是前所未有的，揭示了这种潜在支架的复杂性以及在生物技术和生物学应用中的应用潜力。我们的目标是继续设计IGF2R的结构域，包括结构域9、11和7，以探索它们的小分子（如凝集素结合特性）和对不同同种形式的IGF2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.