Tertiary motifs as building blocks for the design of protein-binding peptides.
Tertiary motifs as building blocks for the design of protein-binding peptides.
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DOI：
10.1002/pro.4322
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发表时间：
2022-06
期刊：
影响因子：
8
通讯作者：
Keating, Amy E.
中科院分区：
文献类型：
--
作者：
Swanson, Sebastian;Sivaraman, Venkatesh;Grigoryan, Gevorg;Keating, Amy E.
关键词：
尽管在蛋白质工程方面取得了进展，但重新设计与所需靶标结合的小蛋白质或肽仍然是一项艰巨的任务。大多数计算方法在候选支架库中搜索结合剂结构，这可能导致靶互补性差和成功率低的设计。我们提出可以构建定制的肽结构来补充靶表面，而不是从预定义的支架中进行选择。我们的方法从已知结构中挖掘三级基序（TERM），以识别表面互补片段或“种子”。我们将满足几何重叠标准的联合收割机种子组合以生成肽骨架并对骨架进行评分以鉴定最可能的结合结构。我们发现基于$TERM的种子可以以高分辨率描述已知的结合结构：来自486种肽蛋白复合物的绝大多数肽结合物可以被单链结构产生的种子覆盖。此外，我们证明了已知的肽结构可以从肽覆盖的种子中以高精度重建。作为概念验证，我们使用我们的方法设计了100种TRAF6的肽结合剂，其中7种被Rosetta预测形成比天然结合剂更高质量的界面。设计的肽与TRAF6上的不同位点相互作用，包括天然肽结合位点。这些结果表明，已知的肽结合结构可以从单链结构的TERMs构建，并表明TERM信息可以用于有效地设计新型靶标互补结合剂。
Despite advances in protein engineering, the de novo design of small proteins or peptides that bind to a desired target remains a difficult task. Most computational methods search for binder structures in a library of candidate scaffolds, which can lead to designs with poor target complementarity and low success rates. Instead of choosing from pre‐defined scaffolds, we propose that custom peptide structures can be constructed to complement a target surface. Our method mines tertiary motifs (TERMs) from known structures to identify surface‐complementing fragments or “seeds.” We combine seeds that satisfy geometric overlap criteria to generate peptide backbones and score the backbones to identify the most likely binding structures. We found that TERM‐based seeds can describe known binding structures with high resolution: the vast majority of peptide binders from 486 peptide‐protein complexes can be covered by seeds generated from single‐chain structures. Furthermore, we demonstrate that known peptide structures can be reconstructed with high accuracy from peptide‐covering seeds. As a proof of concept, we used our method to design 100 peptide binders of TRAF6, seven of which were predicted by Rosetta to form higher‐quality interfaces than a native binder. The designed peptides interact with distinct sites on TRAF6, including the native peptide‐binding site. These results demonstrate that known peptide‐binding structures can be constructed from TERMs in single‐chain structures and suggest that TERM information can be applied to efficiently design novel target‐complementing binders.
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DOI：
10.1083/jcb.201409074
发表时间：
2015-06-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Helma J;Cardoso MC;Muyldermans S;Leonhardt H
通讯作者：
Leonhardt H
DOI：
10.1002/prot.340230412
发表时间：
1995-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Frishman, D;Argos, P
通讯作者：
Argos, P
DOI：
10.1073/pnas.1400419111
发表时间：
2014-02-18
影响因子：
11.1
作者：
Chatzigeorgioua, Antonios;Seijkens, Tom;Lutgens, Esther
通讯作者：
Lutgens, Esther
影响因子：
8
作者：
Frappier, Vincent;Duran, Madeleine;Keating, Amy E.
通讯作者：
Keating, Amy E.
影响因子：
15.9
作者：
Bai, ST;Kitaura, H;Teitelbaum, SL
通讯作者：
Teitelbaum, SL