7STO

Chitin Synthase 2 from Candida albicans bound to polyoxin D

Summary for 7STO

• Entry DOI: 10.2210/pdb7sto/pdb
• EMDB information: 25435
• Descriptor: Chitin synthase, 1,2-Distearoyl-sn-glycerophosphoethanolamine, 1-{(2R,3R,4S,5R)-5-[(S)-{[(2S,3S,4S)-2-amino-5-(carbamoyloxy)-3,4-dihydroxypentanoyl]amino}(carboxy)methyl]-3,4-dihydroxyoxolan-2-yl}-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (non-preferred name) (3 entities in total)
• Functional Keywords: chitin synthesis, glycosyltransferase, polyoxin d, membrane protein, transferase
• Biological source: Candida albicans
• Total number of polymer chains: 2
• Total formula weight: 245623.75

Authors

Ren, Z.,Chhetri, A.,Lee, S.,Yokoyama, K. (deposition date: 2021-11-14, release date: 2022-07-13, Last modification date: 2024-06-05)

Primary citation

Ren, Z.,Chhetri, A.,Guan, Z.,Suo, Y.,Yokoyama, K.,Lee, S.Y.
Structural basis for inhibition and regulation of a chitin synthase from Candida albicans.
Nat.Struct.Mol.Biol., 29:653-664, 2022

PubMed Abstract: 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.

PubMed: 35788183
DOI: 10.1038/s41594-022-00791-x

Experimental method

ELECTRON MICROSCOPY (3.15 Å)