Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Formulation Sciences, MedImmune Ltd., Granta Park, Cambridge, CB21 6GH, UK.
Angew Chem Int Ed Engl. 2016 Nov 2;55(45):14000-14004. doi: 10.1002/anie.201606763. Epub 2016 Oct 13.
Supramolecular interactions between the host cucurbit[8]uril (CB[8]) and amino acids have been widely interrogated, but recognition of specific motifs within a protein domain have never been reported. A phage display approach was herein used to select motifs with the highest binding affinity for the heteroternary complex with methyl viologen and CB[8] (MV⋅CB[8]) within a vast pool of cyclic peptide sequences. From the selected motifs, an epitope consisting of three amino acid was extrapolated and incorporated into a solvent-exposed loop of a protein domain; the protein exhibited micromolar binding affinity for the MV⋅CB[8] complex, matching that of the cyclic peptide. By achieving selective CB[8]-mediated conjugation of a small molecule to a recombinant protein scaffold we pave the way to biomedical applications of this simple ternary system.
主体葫芦脲（CB[8]）与氨基酸之间的超分子相互作用已被广泛研究，但在蛋白质结构域内识别特定基序的情况尚未见报道。本文采用噬菌体展示技术，从庞大的环肽序列库中筛选出与甲基紫精和 CB[8]（MV⋅CB[8]）形成杂合三元复合物时具有最高结合亲和力的基序。从筛选出的基序中，推断出一个由三个氨基酸组成的表位，并将其插入到一个蛋白质结构域的溶剂暴露环中；该蛋白质对 MV⋅CB[8]复合物表现出微摩尔级的结合亲和力，与环肽相当。通过实现小分子与重组蛋白支架的选择性 CB[8]介导偶联，我们为该简单三元体系在生物医学中的应用铺平了道路。
