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TitleCryo-EM structures of Candida albicans chitin synthase Chs1 reveal a druggable translocation channel.
Journal, issue, pagesNat Microbiol, Year 2026
Publish dateSep 15, 2026
AuthorsZhenning Ren / Abhishek Chhetri / Chang Liu / Ziqiang Guan / ShuYu Offner / Dmitry Kozhanov / Mario J Borgnia / Wonpil Im / Kenichi Yokoyama / Seok-Yong Lee /
PubMed AbstractInvasive candidiasis is a leading cause of hospital-acquired bloodstream infections with high mortality. While the fungal cell wall is an excellent therapeutic target, inhibitor development against ...Invasive candidiasis is a leading cause of hospital-acquired bloodstream infections with high mortality. While the fungal cell wall is an excellent therapeutic target, inhibitor development against the essential chitin synthase (Chs) has been hampered by the absence of structural and mechanistic understanding of class II Chs, which contribute to fungal viability. Here we present cryo-electron microscopy structures of Candida albicans class II Chs (CaChs1) at 2.93-3.38 Å resolution, providing insights into its mechanisms of early elongation, chito-oligomer translocation and inhibition by the CaChs1-specific non-competitive inhibitor diynyl arylamine (DA). Chitin elongation and translocation are coupled to coordinated motion of the glycosyltransferase domain and the dimer interface. Notably, DA binds within the chitin translocation channel where a regulatory lipid resides and inhibits the enzyme by occluding product polymer extrusion. Importantly, DA showed potent synergy with the class I Chs inhibitor nikkomycin Z against C. albicans and Candida auris. These findings establish the chitin translocation channel as a druggable site for rational antifungal design.
External linksNat Microbiol / PubMed:42744982 / PubMed Central
MethodsEM (single particle)
Resolution2.85 - 3.38 Å
Structure data

EMDB-76826, PDB-12xf:
Structure of Class II chitin synthase, Chs1, from Candida albicans (CaChs1) in the apo state
Method: EM (single particle) / Resolution: 3.02 Å

EMDB-76827, PDB-12xg:
Structure of Class II chitin synthase, Chs1, from Candida albicans (CaChs1), state 1 (post UDP hydrolysis) after 5 min reaction
Method: EM (single particle) / Resolution: 3.38 Å

EMDB-76828, PDB-12xh:
Structure of Class II chitin synthase, Chs1, from Candida albicans (CaChs1), state 2 (pre-translocation) after 5 min reaction
Method: EM (single particle) / Resolution: 2.93 Å

EMDB-76829, PDB-12xi:
Structure of Class II chitin synthase, Chs1, from Candida albicans (CaChs1), state 3 (post-translocation) after 5 min reaction
Method: EM (single particle) / Resolution: 3.24 Å

EMDB-76830, PDB-12xj:
Structure of Class II chitin synthase, Chs1, from Candida albicans (CaChs1), bound to diynyl arylamine (DA, aka RO-09-3143)
Method: EM (single particle) / Resolution: 2.93 Å

EMDB-76831, PDB-12xk:
Candida albicans Chitin synthase 1 (CaChs1) bound to UDP-GlcNAc and diynyl arylamine (DA, aka RO-09-3143)
Method: EM (single particle) / Resolution: 2.96 Å

EMDB-76832, PDB-12xl:
Candida albicans Chitin synthase 1 (CaChs1) intermediate state (DA-2), bound to UDP and diynyl arylamine (DA, aka RO-09-3143)
Method: EM (single particle) / Resolution: 3.02 Å

EMDB-76833, PDB-12xm:
Candida albicans Chitin synthase 1 (CaChs1) intermediate state (DA-3), bound to UDP and diynyl arylamine (DA, aka RO-09-3143)
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-76834, PDB-12xn:
Candida albicans Chitin synthase 1 (CaChs1) intermediate state (DA-4), bound to UDP and diynyl arylamine (DA, aka RO-09-3143)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-76835, PDB-12xo:
Candida albicans Chitin synthase 1 (CaChs1) intermediate state (DA-5), bound to UDP and diynyl arylamine (DA, aka RO-09-3143)
Method: EM (single particle) / Resolution: 2.85 Å

EMDB-76836, PDB-12xp:
Candida albicans Chitin synthase 1 (CaChs1) intermediate state (DA-6), bound to UDP and diynyl arylamine (DA, aka RO-09-3143)
Method: EM (single particle) / Resolution: 3.29 Å

EMDB-76837, PDB-12xq:
Candida albicans Chitin synthase 1 (CaChs1) intermediate state (DA-7), bound to UDP and diynyl arylamine (DA, aka RO-09-3143)
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM

ChemComp-MG:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-UDP:
URIDINE-5'-DIPHOSPHATE / UDP*YM

ChemComp-HOH:
WATER

PDB-1deh:
CRYSTALLIZATION OF HUMAN BETA1 ALCOHOL DEHYDROGENASE (15 MG/ML) IN 50 MM SODIUM PHOSPHATE (PH 7.5), 2.0 MM NAD+ AND 1 MM 4-IODOPYRAZOLE AT 25 OC, 13% (W/V) PEG 8000

ChemComp-UD1:
URIDINE-DIPHOSPHATE-N-ACETYLGLUCOSAMINE

Source
  • candida albicans (yeast)
KeywordsMEMBRANE PROTEIN / Enzyme / chitin synthesis

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