Structural basis for inhibition and regulation of a chitin synthase from Candida albicans.

Journal Article (Journal Article)

Chitin is an essential component of the fungal cell wall. Chitin synthases (Chss) catalyze chitin formation and translocation across the membrane and are targets of antifungal agents, including nikkomycin Z and polyoxin D. Lack of structural insights into the action of these inhibitors on Chs has hampered their further development to the clinic. We present the cryo-EM structures of Chs2 from Candida albicans (CaChs2) in the apo, substrate-bound, nikkomycin Z-bound, and polyoxin D-bound states. CaChs2 adopts a unique domain-swapped dimer configuration where a conserved motif in the domain-swapped region controls enzyme activity. CaChs2 has a dual regulation mechanism where the chitin translocation tunnel is closed by the extracellular gate and plugged by a lipid molecule in the apo state to prevent non-specific leak. Analyses of substrate and inhibitor binding provide insights into the chemical logic of Chs inhibition, which can guide Chs-targeted antifungal development.

Full Text

Duke Authors

Cited Authors

  • Ren, Z; Chhetri, A; Guan, Z; Suo, Y; Yokoyama, K; Lee, S-Y

Published Date

  • July 2022

Published In

Volume / Issue

  • 29 / 7

Start / End Page

  • 653 - 664

PubMed ID

  • 35788183

Pubmed Central ID

  • PMC9359617

Electronic International Standard Serial Number (EISSN)

  • 1545-9985

Digital Object Identifier (DOI)

  • 10.1038/s41594-022-00791-x

Language

  • eng

Conference Location

  • United States