Homology models of dipeptidyl peptidases 8 and 9 with a focus on loop predictions near the active site
Homology models of dipeptidyl peptidases 8 and 9 with a focus on loop predictions near the active site
复制标题
DOI：
10.1002/prot.21138
复制
发表时间：
2007-01-01
影响因子：
2.9
通讯作者：
Metz, Guenther
中科院分区：
文献类型：
--
作者：
Rummey, Christian;Metz, Guenther
二肽基肽酶4（DP 4）抑制剂目前正在深入研究中的后期临床试验作为11型糖尿病的治疗。缺乏对相关酶DP 8和DP 9的选择性最近已成为药物诱导毒性的可能来源。与DP 4不同的是，DP 8和DP 9的X射线结构尚未获得。为了帮助理解选择性的结构基础，作者基于DP 4的X射线坐标构建了DP 8和DP 9的同源模型。精确的序列比对揭示了共同的结构特征，其指示包含两个结构域的保存良好的整体折叠，即水解酶结构域和所谓的P-推进器，它们一起形成深埋在蛋白质内的活性位点。在这个深腔内部的两个环的构象与活性位点特别相关。作者使用已发表的基于构象采样和能量分析的环路预测方案，为这两个环路生成合理的解决方案。该方法的预测能力成功地评估了模板蛋白DP 4和来自同一蛋白质家族的另外两个已知结构，即FAP和DPX。作者还表明，包含共价配体NVP-728大大增强了细化。基于所建立的评价方案，预测了DP 8和DP 9的相应环，并将所得活性位点与DP 4进行了比较。特别是，作者得出结论，P2口袋的差异与选择性DP 4抑制剂的设计有关。根据其模型预测的DP 8和DP 9中关键相互作用的丧失与DP 4临床候选药物MK-431的选择性特征一致。蛋白质2007;66：160-171。(c)2006 Wiley-Liss，Inc.
Dipeptidyl peptidase 4 (DP4) inhibitors are currently under intensive investigation in late-stage clinical trials as a treatment for type 11 diabetes. Lack of selectivity toward the related enzymes DP8 and DP9 has recently emerged as a possible source of drug-induced toxicity. Unlike DP4, X-ray structures of DP8 and DP9 are not yet available. As an aid to understanding the structural basis for selectivity, the authors have constructed homology models of DP8 and DP9 based on the X-ray coordinates of DP4. Accurate sequence alignment reveals common structural features indicative for a well-preserved overall fold comprising two domains, namely, a hydrolase domain and a so-called P-propeller, which together form the active site deeply buried within the protein. The conformation of two loops inside this deep cavity is particularly relevant for the active sites. The authors used a published protocol for loop prediction based on conformational sampling and energy analysis to generate plausible solutions for these two loops. The predictive power of the approach was successfully evaluated for the template protein DP4 and two additional known structures from the same protein family, namely, FAP and DPX. The authors also show that inclusion of the covalent ligand NVP-728 greatly enhances the refinement. Based on the established evaluation protocol, the corresponding loops of DP8 and DP9 were predicted and the resulting active sites were compared with DP4. In particular, the authors conclude that differences in the P2-pocket are relevant for the design of selective DP4 inhibitors. The loss of key interactions in DP8 and DP9 as predicted from their models is consistent with the selectivity profile of the DP4 clinical candidate MK-431. Proteins 2007;66: 160-171. (c) 2006 Wiley-Liss, Inc.