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Conformational flexibility of a highly conserved helix controls cryptic pocket formation in FtsZ

DOI: 10.1016/j.jmb.2021.167061 DOI Help

Authors: Aisha Alnami (University College London; King Abdulaziz University) , Raymond S. Norton (Monash University) , Helena Perez Pena (University College London) , Shozeb Haider (University College London) , Frank Kozielski (The Beatson Institute for Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology , VOL 433

State: Published (Approved)
Published: July 2021

Abstract: 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.

Journal Keywords: Tuberculosis (TB); Bacteria

Diamond Keywords: Mycobacterium tuberculosis; FtsZ; cryptic pockets; coumarin; antibacterial

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 21/06/2021 15:31

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Drug Discovery Infectious Diseases Pathogens Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)