Conformational flexibility Of A Highly Conserved Helix Controls Cryptic Pocket Formation In FtsZ

Abstract

Mycobacterium tuberculosis is responsible for more than 1.6 million deaths per year. Overcoming failure from established therapies owing to multidrug resistance requires the identification of novel targets. One potential antibacterial target 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 due to the lack of structural information. Here we have solved multiple crystal structures of M. tuberculosis FtsZ in complex with coumarin analogues. Coumarins bind 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 coumarins antibacterial activity.