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首页> 外文期刊>Journal of Molecular Biology >Contributions of CDR3 to V H H domain stability and the design of monobody scaffolds for naive antibody libraries.
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Contributions of CDR3 to V H H domain stability and the design of monobody scaffolds for naive antibody libraries.

机译：CDR3对V H H结构域稳定性的贡献以及用于天然抗体文库的单体支架的设计。

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摘要

Camelids produce functional antibodies devoid of light chains. Autonomous heavy chain variable (V(H)H) domains in these molecules have adapted to the absence of the light chain in the following ways: bulky hydrophobic residues replace small aliphatic residues in the former light chain interface, and residues from the third complementarity-determining region (CDR3) pack against the framework and stabilize the global V(H)H domain fold. To determine the specific roles of CDR3 residues in framework stabilization, we used nai;ve phage-displayed libraries, combinatorial alanine-scanning mutagenesis and biophysical characterization of purified proteins. Our results indicate that in the most stable scaffolds, the structural residues in CDR3 reside near the boundaries of the loop and pack against the framework to form a small hydrophobic core. These results allow us to differentiate between structural CDR3 residues that should remain fixed, and CDR3 residues that are tolerant to substitution and can therefore be varied to generate functional diversity within phage-displayed libraries. These methods and insights can be applied to the rapid design of heavy chain scaffolds for the identification of novel ligands using synthetic, antibody-phage libraries. In addition, they shed light on the relationships between CDR3 sequence diversity and the structural stability of the V(H)H domain fold.
机译：骆驼产生没有轻链的功能性抗体。这些分子中的自主重链可变（V（H）H）结构域通过以下方式适应了轻链的缺失：庞大的疏水残基取代了先前轻链界面中的小脂肪族残基，并且来自第三互补性的残基确定区域（CDR3）紧靠框架包装，并稳定全局V（H）H结构域折叠。为了确定CDR3残基在框架稳定中的特定作用，我们使用了天然噬菌体展示的文库，组合的丙氨酸扫描诱变和纯化蛋白的生物物理表征。我们的结果表明，在最稳定的支架中，CDR3中的结构残基位于环的边界附近并堆积在框架上，形成一个小的疏水核心。这些结果使我们能够区分应保持固定的结构性CDR3残基和耐受取代的CDR3残基，因此可以改变以在噬菌体展示的文库中产生功能多样性。这些方法和见解可用于重链支架的快速设计，以使用合成的抗体噬菌体文库鉴定新的配体。此外，他们阐明了CDR3序列多样性与V（H）H结构域折叠的结构稳定性之间的关系。

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