Conformational Flexibility of A Highly Conserved Helix Controls Cryptic Pocket Formation in FtsZ

JOURNAL OF MOLECULAR BIOLOGY

卷:433

Article

Alnami, Aisha^1,4  Norton, Raymond S.^2,3  Pena, Helena Perez¹  Haider, Shozeb¹  Kozielski, Frank¹ 

[1] UCL, Sch Pharm, Dept Pharmaceut & Biol Chem, 29-39 Brunswick Sq, London WC1N 1AX, England

[2] Monash Univ, Monash Inst Pharmaceut Sci, Med Chem, Parkville, Vic 3052, Australia

[3] Monash Univ, ARC Ctr Fragment Based Design, Parkville, Vic 3052, Australia

[4] King Abdulaziz Univ, Fac Pharm, Dept Pharmaceut Chem, Jeddah 21589, Saudi Arabia

关键词: Mycobacterium tuberculosis;    FtsZ;    cryptic pockets;    coumarin;    antibacterial;   

DOI  :  10.1016/j.jmb.2021.167061

来源: Elsevier

【 摘 要 】

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. (C) 2021 Elsevier Ltd. All rights reserved.

【 授权许可】

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