Structural analysis of leader peptide binding enables leader-free cyanobactin processing.
Structural analysis of leader peptide binding enables leader-free cyanobactin processing.
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DOI：
10.1038/nchembio.1841
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发表时间：
2015-08
影响因子：
14.8
通讯作者：
Naismith JH
中科院分区：
文献类型：
--
作者：
Koehnke J;Mann G;Bent AF;Ludewig H;Shirran S;Botting C;Lebl T;Houssen W;Jaspars M;Naismith JH
在肽的情况下，氨基酸的区域选择性修饰对于许多生物合成途径是常见的，并且许多这样的产物具有作为治疗剂的潜力。ATP依赖性酶LynD在肽底物内将多个半胱氨酸残基杂环化为噻唑啉。该酶需要底物具有保守的N-末端前导序列以获得完全活性。催化作用对底物中紧邻的残基几乎不敏感，这表明识别发生在远离活性位点的地方。LynD的核苷酸和肽底物共复合物结构揭示了底物前导肽结合并延伸LynD的保守结构域的β-折叠，而催化在另一个保守结构域中完成。从识别的空间分离的催化相结合的区域选择性和混杂的看似矛盾的属性，它似乎是一个保守的策略，在其他肽修饰酶。已经工程化了LynD的变体，其在没有前导肽的情况下有效地处理底物。
Regioselective modification of amino acids within the context of a peptide is common to a number of biosynthetic pathways and many such products have potential as therapeutics. The ATP dependent enzyme LynD heterocyclizes multiple cysteine residues to thiazolines within a peptide substrate. The enzyme requires the substrate to have conserved N-terminal leader for full activity. Catalysis is almost insensitive to immediately flanking residues in the substrate suggesting recognition occurs distant from the active site. Nucleotide and peptide substrate co-complex structures of LynD reveal the substrate leader peptide binds to and extends the β-sheet of a conserved domain of LynD, whilst catalysis is accomplished in another conserved domain. The spatial segregation of catalysis from recognition combines seemingly contradictory properties of regioselectivity and promiscuity; it appears to be a conserved strategy in other peptide modifying enzymes. A variant of LynD that efficiently processes substrates without a leader peptide has been engineered.