小柯机器人

美国加州大学圣地亚哥分校Tezcan, F. Akif课题组通过蛋白质设计克服金属选择性的普遍限制。相关论文于2022年3月2日发表在《自然》杂志上。

他们报告了一种人工二聚体蛋白 (AB)2，它在热力学上克服了 Irving-Williams 在体外和细胞中的限制，有利于低 Irving-Williams 过渡金属与 Cu2+（Irving-Williams 系列中最主要的离子）的结合。与分子设计中通过结构预组织实现特异性的惯例相反，(AB)2 被故意设计为灵活的。这种灵活性使 (AB)2 能够采用相互排斥的、金属依赖的构象状态，这导致结构耦合的配位位点发现，并通过强制不利的配位几何结构不利于 Cu2+ 离子结合。除了强调灵活性是蛋白质设计中的重要元素外，他们的结果还说明了构建选择性金属螯合剂的设计原则。

据悉，选择性金属配位是金属蛋白功能的核心：每种金属蛋白都必须与其同源金属因子配对才能发挥其生物学作用。然而，仅通过 3D 蛋白质结构实现金属选择性是一个巨大的挑战，因为金属配位氨基酸功能的集合有限，而蛋白质本身具有灵活性，这阻碍了金属的空间选择。天然蛋白质的金属结合亲和力主要取决于金属离子的电子特性，并遵循 Irving-Williams 系列(Mn2+ < Fe2+ < Co2+ < Ni2+ < Cu2+ > Zn2+)，少数例外。因此，金属蛋白压倒性地结合 Cu2+ 和 Zn2+，不管它们的活性位点的性质和它们的同源金属离子。这导致有机体进化出复杂的稳态机制和非平衡策略，以实现正确的金属形态。

附：英文原文

Title: Overcoming universal restrictions on metal selectivity by protein design

Author: Choi, Tae Su, Tezcan, F. Akif

Issue&Volume: 2022-03-02

Abstract: Selective metal coordination is central to the functions of metalloproteins:1,2 each metalloprotein must pair with its cognate metallocofactor to fulfil its biological role3. However, achieving metal selectivity solely through a three-dimensional protein structure is a great challenge, because there is a limited set of metal-coordinating amino acid functionalities and proteins are inherently flexible, which impedes steric selection of metals3,4. Metal-binding affinities of natural proteins are primarily dictated by the electronic properties of metal ions and follow the Irving–Williams series5 (Mn2+<Fe2+<Co2+<Ni2+<Cu2+>Zn2+) with few exceptions6,7. Accordingly, metalloproteins overwhelmingly bind Cu2+ and Zn2+ in isolation, regardless of the nature of their active sites and their cognate metal ions1,3,8. This led organisms to evolve complex homeostatic machinery and non-equilibrium strategies to achieve correct metal speciation1,3,8,9,10. Here we report an artificial dimeric protein, (AB)2, that thermodynamically overcomes the Irving–Williams restrictions in vitro and in cells, favouring the binding of lower-Irving–Williams transition metals over Cu2+, the most dominant ion in the Irving–Williams series. Counter to the convention in molecular design of achieving specificity through structural preorganization, (AB)2 was deliberately designed to be flexible. This flexibility enabled (AB)2 to adopt mutually exclusive, metal-dependent conformational states, which led to the discovery of structurally coupled coordination sites that disfavour Cu2+ ions by enforcing an unfavourable coordination geometry. Aside from highlighting flexibility as a valuable element in protein design, our results illustrate design principles for constructing selective metal sequestration agents.

DOI: 10.1038/s41586-022-04469-8

Source: https://www.nature.com/articles/s41586-022-04469-8

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