The structure of docking domains in modular polyketide synthases
The structure of docking domains in modular polyketide synthases
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DOI：
10.1016/s1074-5521(03)00156-x
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发表时间：
2003-08-01
影响因子：
--
通讯作者：
Weissman, KJ
中科院分区：
文献类型：
--
作者：
Broadhurst, RW;Nietlispach, D;Weissman, KJ
放线菌细菌中的聚酮化合物为许多有价值的药物提供了基础，因此工程化基因使其生物合成产生变异分子为药物发现带来了希望。模块化聚酮酶特别适合这种方法，因为链延伸的每个循环由不同的酶模块催化，并且模块以它们作用的顺序排列在巨大的多酶亚单位内。连续多酶的末端对接结构域之间的蛋白质-蛋白质相互作用促进它们在装配线内的正确定位，但由于整体复合物在体外不稳定，因此关键的相互作用尚未确定。我们在这里提出的NMR溶液结构的120个残基的多肽代表一个典型的对这样的结构域，在其各自的C和N末端融合：它采用了一个稳定的二聚体结构，揭示了详细的作用，这些{主要是螺旋}结构域的对接和二聚化模块化聚酮酶。
Polyketides from actinomycete bacteria provide the basis for many valuable medicines, so engineering genes for their biosynthesis to produce variant molecules holds promise for drug discovery. The modular polyketide synthases are particularly amenable to this approach, because each cycle of chain extension is catalyzed by a different module of enzymes, and the modules are arranged within giant multienzyme sub-units in the order in which they act. Protein-protein interactions between terminal docking domains of successive multienzymes promote their correct positioning within the assembly line, but because the overall complex is not stable in vitro, the key interactions have not been identified. We present here the NMR solution structure of a 120 residue polypeptide representing a typical pair of such domains, fused at their respective C and N termini: it adopts a stable dimeric structure which reveals the detailed role of these {predominantly helical} domains in docking and dimerization by modular polyketide synthases.