Structural basis for the binding of didemnins to human elongation factor eEF1A and rationale for the potent antitumor activity of these marine natural products
Structural basis for the binding of didemnins to human elongation factor eEF1A and rationale for the potent antitumor activity of these marine natural products
复制标题
DOI：
10.1021/jm0306428
复制
发表时间：
2004-08-26
影响因子：
7.3
通讯作者：
Gago, F
中科院分区：
文献类型：
--
作者：
Marco, E;Martín-Santamaría, S;Gago, F
Didemnins和tamandarins是密切相关的海洋天然产物，对蛋白质合成和细胞活力具有强效抑制作用。现有的生物化学和结构的证据和分子动力学模拟的结果的基础上，提出了一个模型，占这些化合物的强大和选择性结合到人的延伸因子eEF 1A在GTP的存在下。我们认为，这些环状缩酚酸肽的p-甲氧基苯基环被插入eEF 1A中的相同口袋中，该口袋通常容纳氨酰化tRNA的3'末端腺嘌呤，如从两个原核EF-Tu（.）GTP-tRNA复合物，或来自核苷酸交换因子eEF 1B α的Phe/Tyr-163的芳香族侧链，如在酵母eEF 1A：eEF 1B α复合物的几种X射线晶体结构中观察到的。该口袋具有很强的疏水性，由eEF 1A结构域2表面上的两个突出环形成。通过涉及eEF 1A结构域1的额外关键相互作用，使分子紧密地贴合在这两个结构域之间的界面处，从而进一步稳定结合的缩肽。在eEF 1A的GDP结合形式中，该结合位点仅以两个独立的一半存在，这解释了didemnins对该延伸因子的GDP结合形式的亲和力要大得多。这种结合模式与同源原核EF-Tu与kirromycin型抗生素或环噻唑基肽抗生素GE 2270 A的复合物中所见的完全不同。有趣的是，didemnins与eEF 1A结合所使用的相互作用也与eEF 1B α或eEF 1B β所使用的相互作用不同，因此建立了一种超越简单分子模拟的结合共同位点的竞争。这里提出的模型与现有的生物化学证据和已知的结构-活性关系，这两类天然化合物和合成类似物是一致的，并为未来的研究提供了肥沃的土壤。
Didemnins and tamandarins are closely related marine natural products with potent inhibitory effects on protein synthesis and cell viability. On the basis of available biochemical and structural evidence and results from molecular dynamics simulations, a model is proposed that accounts for the strong and selective binding of these compounds to human elongation factor eEF1A in the presence of GTP. We suggest that the p-methoxyphenyl ring of these cyclic depsipeptides is inserted into the same pocket in eEF1A that normally lodges either the 3' terminal adenine of aminoacylated tRNA, as inferred from two prokaryotic EF-Tu(.)GTP-tRNA complexes, or the aromatic side chain of Phe/Tyr-163 from the nucleotide exchange factor eEF1Balpha, as observed in several X-ray crystal structures of a yeast eEF1A:eEF1Balpha complex. This pocket, which has a strong hydrophobic character, is formed by two protruding loops on the surface of eEF1A domain 2. Further stabilization of the bound depsipeptide is brought about by additional crucial interactions involving eEF1A domain 1 in such a way that the molecule fits snugly at the interface between these two domains. In the GDP-bound form of eEF1A, this binding site exists only as two separate halves, which accounts for the much greater affinity of didemnins for the GTP-bound form of this elongation factor. This binding mode is entirely different from those seen in the complexes of the homologous prokaryotic EF-Tu with kirromycin-type antibiotics or the cyclic thiazolyl peptide antibiotic GE2270A. Interestingly, the set of interactions used by didemnins to bind to eEF1A is also distinct from that used by eEF1Balpha or eEF1Bbeta, thus establishing a competition for binding to a common site that goes beyond simple molecular mimicry. The model presented here is consistent with both available biochemical evidence and known structure-activity relationships for these two classes of natural compounds and synthetic analogues and provides fertile ground for future research.