Meditope-Fab interaction: threading the hole.
Meditope-Fab interaction: threading the hole.
复制标题
Mediope-Fab 相互作用：穿入孔。
DOI：
10.1107/s2053230x17016272
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Williams,JohnC
中科院分区：
文献类型：
--
作者：
Bzymek,KrzysztofP;Ma,Yuelong;Avery,KendraN;Horne,DavidA;Williams,JohnC
中间位是一种环状12残基肽，与西妥昔单抗Fab轻链和重链之间的独特结合侧结合。为了提高相互作用的亲和力，试图延长中间位中Arg8的侧链，以增加相互作用的数量，所述中间位是可从中间位结合位点的另一侧接近的残基。这些修饰包括正丁基和正辛基延伸以及羟基、胺和羧基取代。复合物的原子结构和每个修饰的中间位的结合动力学表明，每个延伸穿过Fab“孔”，并且羧乙基精氨酸取代与Fab形成有利的相互作用，与未修饰的中间位相比，复合物的半衰期增加了三倍。总之，这些研究为设计额外的修饰以增强这种独特相互作用的总体亲和力提供了基础。
Meditope, a cyclic 12-residue peptide, binds to a unique binding side between the light and heavy chains of the cetuximab Fab. In an effort to improve the affinity of the interaction, it was sought to extend the side chain of Arg8 in the meditope, a residue that is accessible from the other side of the meditope binding site, in order to increase the number of interactions. These modifications included an n-butyl and n-octyl extension as well as hydroxyl, amine and carboxyl substitutions. The atomic structures of the complexes and the binding kinetics for each modified meditope indicated that each extension threaded through the Fab `hole' and that the carboxyethylarginine substitution makes a favorable interaction with the Fab, increasing the half-life of the complex by threefold compared with the unmodified meditope. Taken together, these studies provide a basis for the design of additional modifications to enhance the overall affinity of this unique interaction.