Dipeptidyl peptidase-IV (DPP-IV) inhibiting peptides have attracted increased attention because of their possible beneficial effects on glycemic homeostasis. However, the structural basis underpinning their activities has not been well understood. This study combined computational and in vitro investigations to explore the structural basis of DPP-IV inhibitory peptides. We first superimposed the Xaa–Pro-type peptide-like structures from several crystal structures of DPP-IV ligand–protein complexes to analyze the recognition interactions of DPP-IV to peptides. Thereafter, a small set of Xaa–Pro-type peptides was designed to explore the effect of key interactions on inhibitory activity. The intramolecular interaction of Xaa–Pro-type peptides at the first and third positions from the N-terminus was pivotal to their inhibitory activities. Residue interactions between DPP-IV and residues of the peptides at the fourth and fifth positions of the N-terminus contributed significantly to the inhibitory effect of Xaa–Pro-type tetrapeptides and pentapeptides. Based on the interaction descriptors, quantitative structure–activity relationship (QSAR) studies with the DPP-IV inhibitory peptides resulted in valid models with high R² values (0.90 for tripeptides; 0.91 for tetrapeptides and pentapeptides) and Q² values (0.33 for tripeptides; 0.68 for tetrapeptides and pentapeptides). Taken together, the structural information on DPP-IV and peptides in this study facilitated the development of novel DPP-IV inhibitory peptides.

中文翻译：

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对二肽基肽酶 IV 抑制肽的分子机制洞察，以破译活性的结构基础

二肽基肽酶-IV (DPP-IV) 抑制肽因其可能对血糖稳态产生有益作用而引起了越来越多的关注。然而，支撑其活动的结构基础尚未得到充分了解。本研究结合计算和体外研究来探索 DPP-IV 抑制肽的结构基础。我们首先将来自 DPP-IV 配体-蛋白质复合物的几种晶体结构的 Xaa-Pro 型肽样结构叠加起来，以分析 DPP-IV 与肽的识别相互作用。此后，设计了一小组 Xaa-Pro 型肽来探索关键相互作用对抑制活性的影响。 Xaa-Pro 型肽在 N 末端第一个和第三个位置上的分子内相互作用对其抑制活性至关重要。 DPP-IV 与 N 末端第四位和第五位的肽残基之间的残基相互作用对 Xaa-Pro 型四肽和五肽的抑制作用有显着贡献。基于相互作用描述符，使用 DPP-IV 抑制肽进行的定量构效关系 (QSAR) 研究产生了具有高R ²值（三肽为 0.90；四肽和五肽为 0.91）和Q ²值（三肽为 0.33）的有效模型。 ；四肽和五肽为 0.68）。总而言之，本研究中 DPP-IV 和肽的结构信息促进了新型 DPP-IV 抑制肽的开发。