Ligand selectivity and competition between enzymes in silico
Ligand selectivity and competition between enzymes in silico
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DOI：
10.1038/nbt999
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发表时间：
2004-08-01
影响因子：
46.9
通讯作者：
Thornton, JM
中科院分区：
文献类型：
--
作者：
Macchiarulo, A;Nobeli, I;Thornton, JM
在细胞中，酶和小分子之间存在许多交叉相互作用的可能性，这是由于代谢物结构的相似性和蛋白质活性位点结合的灵活性。尽管这种混杂，同源伴侣必须能够在体内相互识别，以使细胞有效地发挥作用。本研究探讨了这种选择性的识别使用标准的对接计算的基础上，发现显着改善时，蛋白质和配体的交叉对接。我们发现，同源分子很少形成最稳定的复合物，特异性可能是由酶识别底物或由底物识别酶驱动的。尽管计算机模拟方法存在局限性，特别是评分功能，但这些计算强调了考虑细胞中交叉反应的必要性，并表明定位和区室化必须是复杂细胞进化中的重要因素。然而，这些相互作用的内在混杂性也可以通过促进旧功能的新功能的进化而使生物体受益。研究结果还表明，高通量筛选不应该只涉及一组小分子，还应该涉及一组蛋白质来测试交叉反应性。
In a cell, there are many possibilities for cross interactions between enzymes and small molecules, arising from the similarities in the structures of the metabolites and the flexibility in binding of protein active sites. Despite this promiscuity, the cognate partners must be able to recognize each other in vivo, for the cell to function efficiently. This study examines the basis of this selectivity in recognition using standard docking calculations and finds significant improvement when proteins and ligands are cross-docked. We find that cognate molecules rarely form the most stable complexes and that specificity may be driven either by recognition of the substrate by the enzyme or the recognition of the enzyme by the substrate. Despite limitations of the in silico methods, especially the scoring functions, these calculations highlight the need to consider cross reactions in the cell and suggest that localization and compartmentalization must be important factors in the evolution of complex cells. However, the inherent promiscuity of these interactions can also benefit an organism, by facilitating the evolution of new functions from old ones. The results also suggest that high-throughput screening should involve not just a panel of small molecules, but also a panel of proteins to test for cross-reactivity.