Ligand tunnels in T. brucei and human CYP51: Insights for parasite-specific drug design.
Ligand tunnels in T. brucei and human CYP51: Insights for parasite-specific drug design.
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T. brucei 和人类 CYP51 中的配体隧道：寄生虫特异性药物设计的见解。
DOI：
10.1016/j.bbagen.2015.10.015
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Wade,RebeccaC
中科院分区：
文献类型：
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作者：
Yu,Xiaofeng;Nandekar,Prajwal;Mustafa,Ghulam;Cojocaru,Vlad;Lepesheva,GalinaI;Wade,RebeccaC
背景细胞色素P450甾醇14α-去甲基酶（CYP51）是甾醇生物合成的必需酶，也是抗寄生虫药物设计的靶标。然而，设计抑制寄生虫 CYP51 而没有严重副作用的寄生虫特异性药物仍然具有挑战性。 CYP51 的活性位点位于蛋白质的内部。在这里，我们描述了布氏锥虫和人类 CYP51 酶中潜在的配体流出途径和机制。方法我们对四种不同配体从可溶性和膜结合 T 模型的活性位点的流出进行了随机加速分子动力学模拟。 bruceiCYP51 和可溶性人 CYP51。结果在模拟中，通向膜的隧道 2f 被发现是所有研究配体的主要配体出口隧道。通向细胞质的隧道 S、1 和 W 也用于 T。 bruceiCYP51，而隧道 1 是唯一在人类 CYP51 中显着使用的其他隧道。以前在其他 CYP 中发现的公共隧道几乎没有被使用。人类的配体流出时间比T短。 bruceiCYP51，表明配体通过的障碍较低。两个门控残基，F105 和 M460，inT。鉴定出调节隧道 2 f 和 S 开口的 bruceiCYP51。 结论 尽管主要出口隧道相同，但 T 之间的隧道衬砌残留物、配体通道和隧道使用方面存在差异。布鲁斯和人CYP51。一般意义该结果为设计针对配体通道的选择性抗寄生虫药物提供了基础。
BackgroundCytochrome P450 sterol 14α-demethylase (CYP51) is an essential enzyme for sterol biosynthesis and a target for anti-parasitic drug design. However, the design of parasite-specific drugs that inhibit parasitic CYP51 without severe side effects remains challenging. The active site of CYP51 is situated in the interior of the protein. Here, we characterize the potential ligand egress routes and mechanisms inTrypanosoma bruceiand human CYP51 enzymes.MethodsWe performed Random Acceleration Molecular Dynamics simulations of the egress of four different ligands from the active site of models of soluble and membrane-boundT. bruceiCYP51 and of soluble human CYP51.ResultsIn the simulations, tunnel 2 f, which leads to the membrane, was found to be the predominant ligand egress tunnel for all the ligands studied. Tunnels S, 1 and W, which lead to the cytosol, were also used inT. bruceiCYP51, whereas tunnel 1 was the only other tunnel used significantly in human CYP51. The common tunnels found previously in other CYPs were barely used. The ligand egress times were shorter for human thanT. bruceiCYP51, suggesting lower barriers to ligand passage. Two gating residues, F105 and M460, inT. bruceiCYP51 that modulate the opening of tunnels 2 f and S were identified.ConclusionsAlthough the main egress tunnel was the same, differences in the tunnel-lining residues, ligand passage and tunnel usage were found betweenT. bruceiand human CYP51s.General SignificanceThe results provide a basis for the design of selective anti-parasitic agents targeting the ligand tunnels.