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首页> 外文期刊>ACS Omega >Homology Modeling of Human Uridine-5′-diphosphate-glucuronosyltransferase 1A6 Reveals Insights into Factors Influencing Substrate and Cosubstrate Binding
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Homology Modeling of Human Uridine-5′-diphosphate-glucuronosyltransferase 1A6 Reveals Insights into Factors Influencing Substrate and Cosubstrate Binding

机译：人尿苷5'-二磷酸-葡萄糖醛酸转移酶1A6的同源性建模揭示洞察到影响基质和共基质结合的因素。

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摘要

The elimination of numerous endogenous compounds and xenobiotics via glucuronidation by uridine-5′-diphosphate glycosyltransferase enzymes (UGTs) is an essential process of the body’s chemical defense system. UGTs have distinct but overlapping substrate preferences, but the molecular basis for their substrate specificity remains poorly understood. Three-dimensional protein structures can greatly enhance our understanding of the interactions between enzymes and their substrates, but because of the inherent difficulties in purifying and crystallizing integral endoplasmic reticulum membrane proteins, no complete mammalian UGT structure has yet been produced. To address this problem, we have created a homology model of UGT1A6 using I-TASSER to explore, in detail, the interactions of human UGT1A6 with its substrates. Ligands were docked into our model in the presence of the cosubstrate uridine-5′-diphosphate-glucuronic acid, interacting residues were examined, and poses were compared to those cocrystallized with various plant and bacterial glycosyltransferases (GTs). Our model structurally resembles other GTs, and docking experiments replicated many of the expected UGT-substrate interactions. Some bias toward the template structures’ protein–substrate interactions and binding preferences was evident.
机译：尿苷5'-二磷酸糖基转移酶（UGT）通过葡萄糖醛酸糖苷化消除许多内源性化合物和异种生物是人体化学防御系统的重要过程。 UGT具有独特但重叠的底物偏好，但对其底物特异性的分子基础仍知之甚少。三维蛋白质结构可以极大地增进我们对酶及其底物之间相互作用的理解，但是由于纯化和结晶完整的内质网膜蛋白存在固有的困难，因此尚未产生完整的哺乳动物UGT结构。为了解决这个问题，我们使用I-TASSER创建了一个UGT1A6同源模型，以详细研究人UGT1A6与它的底物之间的相互作用。在存在共底物尿苷5'-二磷酸-葡萄糖醛酸的情况下，将配体对接到我们的模型中，检查相互作用的残基，并将其与与各种植物和细菌糖基转移酶（GTs）共结晶的那些进行比较。我们的模型在结构上与其他GT相似，并且对接实验复制了许多预期的UGT与底物之间的相互作用。明显偏向于模板结构的蛋白质-底物相互作用和结合偏好。

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