Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
Mar Drugs. 2020 May 14;18(5):256. doi: 10.3390/md18050256.
Conotoxins are short, cysteine-rich peptides of great interest as novel therapeutic leads and of great concern as lethal biological agents due to their high affinity and specificity for various receptors involved in neuromuscular transmission. Currently, of the approximately 6000 known conotoxin sequences, only about 3% have associated structural characterization, which leads to a bottleneck in rapid high-throughput screening (HTS) for identification of potential leads or threats. In this work, we combine a graph-based approach with homology modeling to expand the library of conotoxin structures and to identify those conotoxin sequences that are of the greatest value for experimental structural characterization. The latter would allow for the rapid expansion of the known structural space for generating high quality template-based models. Our approach generalizes to other evolutionarily-related, short, cysteine-rich venoms of interest. Overall, we present and validate an approach for venom structure modeling and experimental guidance and employ it to produce a 290%-larger library of approximate conotoxin structures for HTS. We also provide a set of ranked conotoxin sequences for experimental structure determination to further expand this library.
短肽毒素(conotoxin)富含半胱氨酸，具有很大的研究价值，可作为新型治疗靶点；同时，由于其对参与神经肌肉传递的各种受体具有高亲和力和特异性，因此也是致命的生物制剂，令人深感担忧。目前，在已知的大约 6000 种短肽毒素序列中，仅有约 3%具有相关的结构特征描述，这导致在快速高通量筛选 (HTS) 中识别潜在的治疗靶点或威胁方面存在瓶颈。在这项工作中，我们结合基于图的方法和同源建模来扩展短肽毒素结构库，并确定那些对于实验结构特征描述最有价值的短肽毒素序列。后者可以快速扩展已知结构空间，生成高质量基于模板的模型。我们的方法可以推广到其他具有进化相关性的、短的、富含半胱氨酸的相关毒液。总的来说，我们提出并验证了一种毒液结构建模和实验指导的方法，并将其应用于产生更大的 290%的短肽毒素结构近似文库，用于 HTS。我们还提供了一组经过排序的短肽毒素序列，用于实验结构测定，以进一步扩展这个文库。
