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Structural basis for inhibition and regulation of a chitin synthase from Candida albicans
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Structural basis for inhibition and regulation of a chitin synthase from Candida albicans
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Journal Article
Structural basis for inhibition and regulation of a chitin synthase from Candida albicans
2022
Overview
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
(
Ca
Chs2) in the apo, substrate-bound, nikkomycin Z-bound, and polyoxin D-bound states.
Ca
Chs2 adopts a unique domain-swapped dimer configuration where a conserved motif in the domain-swapped region controls enzyme activity.
Ca
Chs2 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.
Atomic-resolution structures of an important antifungal target, chitin synthase 2, from a pathogenic fungus,
Candida albicans
, reveal a unique domain-swapped dimeric assembly and provide insights into the mechanism of antifungal action.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 101/58
/ 64
/ 82
/ 82/80
/ 82/83
/ Antifungal Agents - chemistry
/ Antifungal Agents - metabolism
/ Antifungal Agents - pharmacology
/ Biochemistry & Molecular Biology
/ Biomedical and Life Sciences
/ Candida albicans - metabolism
/ Chitin
/ Chitin Synthase - metabolism
/ Domains
/ Fungi
/ Lipids
/ Polymers
/ Polyoxin
