Bosshart Patrick D, Kalbermatter David, Bonetti Sara, Fotiadis Dimitrios
Institute of Biochemistry and Molecular Medicine, and Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Bern, Switzerland.
leadXpro AG, Park Innovare, Villigen, Switzerland.
Commun Chem. 2021 Sep 6;4(1):128. doi: 10.1038/s42004-021-00564-5.
L-lactate is an important metabolite, energy source, and signaling molecule in health and disease. In mammals, its transport across biological membranes is mediated by monocarboxylate transporters (MCTs) of the solute carrier 16 (SLC16) family. Malfunction, overexpression or absence of transporters of this family are associated with diseases such as cancer and type 2 diabetes. Moreover, lactate acts as a signaling molecule and virulence factor in certain bacterial infections. Here, we report the rational, structure-guided identification of potent, nanomolar affinity inhibitors acting on an L-lactate-specific SLC16 homologue from the bacterium Syntrophobacter fumaroxidans (SfMCT). High-resolution crystal structures of SfMCT with bound inhibitors uncovered their interaction mechanism on an atomic level and the role of water molecules in inhibitor binding. The presented systematic approach is a valuable procedure for the identification of L-lactate transport inhibitors. Furthermore, identified inhibitors represent potential tool compounds to interfere with monocarboxylate transport across biological membranes mediated by MCTs.
L-乳酸是健康和疾病状态下一种重要的代谢物、能量来源及信号分子。在哺乳动物中，其跨生物膜的转运由溶质载体16（SLC16）家族的单羧酸转运蛋白（MCTs）介导。该家族转运蛋白的功能异常、过表达或缺失与癌症和2型糖尿病等疾病相关。此外，乳酸在某些细菌感染中作为信号分子和毒力因子发挥作用。在此，我们报告了基于理性设计、结构导向鉴定出的对来自富马酸氧化互营杆菌（SfMCT）的L-乳酸特异性SLC16同源物具有纳摩尔亲和力的强效抑制剂。结合抑制剂的SfMCT的高分辨率晶体结构揭示了它们在原子水平上的相互作用机制以及水分子在抑制剂结合中的作用。所展示的系统方法是鉴定L-乳酸转运抑制剂的宝贵程序。此外，鉴定出的抑制剂代表了潜在的工具化合物，可用于干扰由MCTs介导的单羧酸跨生物膜的转运。
