Creation of a S1P Lyase bacterial surrogate for structure-based drug design
Creation of a S1P Lyase bacterial surrogate for structure-based drug design
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DOI：
10.1016/j.bmcl.2016.02.084
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发表时间：
2016-05-01
影响因子：
2.7
通讯作者：
Harris, Christopher M.
中科院分区：
文献类型：
--
作者：
Argiriadi, Maria A.;Banach, David;Harris, Christopher M.
S1P裂解酶（SPL）已被描述为治疗自身免疫性疾病的药物靶点。它在维持细胞内S1P水平从而影响T细胞从淋巴组织的输出中起重要作用。几个研究小组已经发表了用小分子抑制S1P裂解酶的方法，这反过来增加内源性S1P浓度，导致免疫抑制。结构生物学的应用已经帮助了SPL抑制剂的设计。新颖的结构设计有时是必要的，为蛋白质晶体学提供试剂。在这里，我们提出了一种嵌合细菌蛋白质支架，用于早期小分子抑制剂存在下的蛋白质x射线结构。从嗜热共生菌中引入了类似人类酶的细菌SPL突变。结果，两个突变体StSPL晶体结构的分辨率分别为2.8埃和2.2埃，并为异恶唑化学系列提供了初步的结构假设，本文将对其优化进行讨论。(C) 2016 Elsevier Ltd.版权所有。
S1P Lyase (SPL) has been described as a drug target in the treatment of autoimmune diseases. It plays an important role in maintaining intracellular levels of S1P thereby affecting T cell egress from lymphoid tissues. Several groups have already published approaches to inhibit S1P Lyase with small molecules, which in turn increase endogenous S1P concentrations resulting in immunosuppression. The use of structural biology has previously aided SPL inhibitor design. Novel construct design is at times necessary to provide a reagent for protein crystallography. Here we present a chimeric bacterial protein scaffold used for protein X-ray structures in the presence of early small molecule inhibitors. Mutations were introduced to the bacterial SPL from Symbiobacterium thermophilum which mimic the human enzyme. As a result, two mutant StSPL crystal structures resolved to 2.8 angstrom and 2.2 angstrom resolutions were solved and provide initial structural hypotheses for an isoxazole chemical series, whose optimization is discussed in the accompanying paper. (C) 2016 Elsevier Ltd. All rights reserved.