Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia; ARC Centre for Fragment-Based Design, Monash University, Parkville, Victoria, 3052, Australia.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.
Toxicon. 2021 Oct 15;201:127-140. doi: 10.1016/j.toxicon.2021.08.020. Epub 2021 Aug 26.
Peptide toxins are potent and often exquisitely selective probes of the structure and function of ion channels and receptors, and are therefore of significant interest to the pharmaceutical and biotech industries as both pharmacological tools and therapeutic leads. The three-dimensional structures of peptide toxins are essential as a basis for understanding their structure-activity relationships and their binding to target receptors, as well as in guiding the design of analogues with modified potency and/or selectivity for key targets. NMR spectroscopy has played a key role in elucidating the structures of peptide toxins and probing their structure-function relationships. In this article, we highlight the additional important contribution of NMR to characterising the dynamics of peptide toxins. We also compare the information available from NMR measurements with that afforded by molecular dynamics simulations. We describe several examples of the importance of dynamics measurements over a range of timescales for understanding the structure-function relationships of peptide toxins and their receptor engagement. Peptide toxins that inhibit the voltage-gated potassium channel K1.3 with pM affinities display different degrees of conformational flexibility, even though they contain multiple disulfide bonds, and this flexibility can affect the relative orientation of residues that have been shown to be critical for channel binding. Information on the dynamic properties of peptide toxins is important in the design of analogues or mimetics where receptor-bound structures are not available.
肽毒素是研究离子通道和受体结构和功能的有效且选择性探针，因此，肽毒素作为药理学工具和治疗先导物，受到制药和生物技术行业的极大关注。了解其结构-活性关系及其与靶受体的结合，以及指导设计具有关键靶标改变的效力和/或选择性的类似物，都需要了解肽毒素的三维结构。NMR 光谱学在阐明肽毒素的结构和探测其结构-功能关系方面发挥了关键作用。在本文中，我们强调了 NMR 在描绘肽毒素动力学方面的重要补充作用。我们还比较了 NMR 测量提供的信息与分子动力学模拟提供的信息。我们描述了几个例子，说明了在不同时间尺度上测量动力学对理解肽毒素的结构-功能关系及其与受体的结合的重要性。以皮摩尔亲和力抑制电压门控钾通道 K1.3 的肽毒素，即使含有多个二硫键，也表现出不同程度的构象灵活性，这种灵活性会影响已被证明对通道结合至关重要的残基的相对取向。关于肽毒素动态特性的信息对于设计类似物或模拟物非常重要，因为这些类似物或模拟物中没有受体结合的结构。
