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首页> 外文期刊>Journal of Molecular Biology >Selection of High-Affinity Peptidic Serine Protease Inhibitors with Increased Binding Entropy from a Back-Flip Library of Peptide-Protease Fusions
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Selection of High-Affinity Peptidic Serine Protease Inhibitors with Increased Binding Entropy from a Back-Flip Library of Peptide-Protease Fusions

机译：从肽蛋白酶融合物的后空库中选择具有增加结合熵的高亲和力肽丝氨酸蛋白酶抑制剂

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摘要

We have developed a new concept for designing peptidic protein modulators, by recombinantly fusing the peptidic modulator, with randomized residues, directly to the target protein via a linker and screening for internal modulation of the activity of the protein. We tested the feasibility of the concept by fusing a 10-residue-long, disulfide-bond-constrained inhibitory peptide, randomized in selected positions, to the catalytic domain of the serine protease murine urokinase-type plasminogen activator. High-affinity inhibitory peptide variants were identified as those that conferred to the fusion protease the lowest activity for substrate hydrolysis. The usefulness of the strategy was demonstrated by the selection of peptidic inhibitors of murine urokinase-type plasminogen activator with a low nanomolar affinity. The high affinity could not have been predicted by rational considerations, as the high affinity was associated with a loss of polar interactions and an increased binding entropy. (C) 2015 Elsevier Ltd. All rights reserved.
机译：我们已经开发了一种设计肽蛋白调节剂的新概念，方法是将肽调节剂与随机残基通过接头重组融合到目标蛋白上，并筛选蛋白活性的内部调节方法。我们通过将随机分布在选定位置的10个残基长，二硫键受限的抑制肽与丝氨酸蛋白酶鼠尿激酶型纤溶酶原激活剂的催化域融合，测试了该概念的可行性。高亲和力抑制肽变体被鉴定为那些赋予融合蛋白酶底物水解最低活性的变体。选择具有低纳摩尔摩尔亲和力的鼠尿激酶型纤溶酶原激活剂的肽类抑制剂证明了该策略的有效性。高亲和力无法通过理性考虑进行预测，因为高亲和力与极性相互作用的丧失和结合熵的增加相关。 （C）2015 Elsevier Ltd.保留所有权利。

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