Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.
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.
J Mol Biol. 2021 Jul 23;433(15):167061. doi: 10.1016/j.jmb.2021.167061. Epub 2021 May 21.
Mycobacterium tuberculosis is responsible for more than 1.6 million deaths each year. One potential antibacterial target in M. tuberculosis is filamentous temperature sensitive protein Z (FtsZ), which is the bacterial homologue of mammalian tubulin, a validated cancer target. M. tuberculosis FtsZ function is essential, with its inhibition leading to arrest of cell division, elongation of the bacterial cell and eventual cell death. However, the development of potent inhibitors against FtsZ has been a challenge owing to the lack of structural information. Here we report multiple crystal structures of M. tuberculosis FtsZ in complex with a coumarin analogue. The 4-hydroxycoumarin binds exclusively to two novel cryptic pockets in nucleotide-free FtsZ, but not to the binary FtsZ-GTP or GDP complexes. Our findings provide a detailed understanding of the molecular basis for cryptic pocket formation, controlled by the conformational flexibility of the H7 helix, and thus reveal an important structural and mechanistic rationale for coumarin antibacterial activity.
结核分枝杆菌每年导致超过 160 万人死亡。分枝杆菌中的一个潜在的抗菌靶标是丝状温度敏感蛋白 Z（FtsZ），它是哺乳动物微管蛋白的细菌同源物，微管蛋白是一个已验证的癌症靶点。分枝杆菌 FtsZ 的功能是必不可少的，其抑制作用导致细胞分裂停滞、细菌细胞伸长，最终导致细胞死亡。然而，由于缺乏结构信息，针对 FtsZ 的有效抑制剂的开发一直是一个挑战。在这里，我们报告了分枝杆菌 FtsZ 与香豆素类似物结合的多个晶体结构。4-羟基香豆素仅与无核苷酸 FtsZ 中的两个新的隐匿口袋结合，而不与二元 FtsZ-GTP 或 GDP 复合物结合。我们的研究结果提供了对隐匿口袋形成的分子基础的详细了解，这是由 H7 螺旋的构象灵活性控制的，因此揭示了香豆素抗菌活性的重要结构和机制基础。
