Structural basis for the cyclization of the lipopeptide antibiotic surfactin by the thioesterase domain SrfTE
Structural basis for the cyclization of the lipopeptide antibiotic surfactin by the thioesterase domain SrfTE
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DOI：
10.1016/s0969-2126(02)00716-5
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发表时间：
2002-03-01
期刊：
影响因子：
5.7
通讯作者：
Stubbs, MT
中科院分区：
文献类型：
--
作者：
Bruner, SD;Weber, T;Stubbs, MT
许多具有生物活性的天然多肽都是由非核糖体肽合成酶(NRPS)合成的。产物的释放是通过特定的硫代酯酶(TE)结构域完成的，其中一些结构域催化分子内环化形成大内酯或大内酰胺环肽。切割的28 kDa SrfTE结构域是α/β水解酶家族的成员之一，它显示出一个独特的碗状疏水空腔，承载着酰基肽底物，并容忍其折叠形成环状结构。底物类似物确认了底物结合部位，并提出了底物酰化/脱酰化的机制。将肽基载体蛋白结构域对接在SrfTE之前，定位4‘-磷酸丙硫基假体基团，该基团将新生的酰基肽链转移到sRfTE。该结构为了解酰基PCP底物识别机理和环化反应释放大内酯环七肽提供了基础。
Many biologically active natural peptides are synthesized by nonribosomal peptide synthetases (NRPS). Product release is accomplished by dedicated thioesterase (TE) domains, some of which catalyze an intramolecular cyclization to form macrolactone or macrolactam cyclic peptides. The excised 28 kDa SrfTE domain, a member of the alpha/beta hydrolase enzyme family, exhibits a distinctive bowl-shaped hydrophobic cavity that hosts the acylpeptide substrate and tolerates its folding to form a cyclic structure. A substrate analog confirms the substrate binding site and suggests a mechanism for substrate acylation/deacylation. Docking of the peptidyl carrier protein domain immediately preceding SrfTE positions the 4'-phosphopantheinyl prosthetic group that transfers the nascent acyl-peptide chain to SrfTE. The structure provides a basis for understanding the mechanism of acyl-PCP substrate recognition and for the cyclization reaction that results in release of the macrolactone cyclic heptapeptide.