Now, using cryo-electron microscopy, Hu et al. have determined the structure of FKS1 from Saccharomyces cerevisiae. FKS1 consists of a wedge-shaped transmembrane (TM) domain of 17 helices, cytoplasmic GT and accessory (AC) domains, and several unstructured extracellular loops. The TM domain contains multiple bound lipids that probably contribute to stabilization, as well as a pair of pockets, one each on the intracellular and extracellular sides, that form a likely path for glucan translocation. The active site of FKS1 is located within a solvent-exposed chamber formed by the GT domain and the TM domain at the membrane–cytoplasm interface.
Notably, the substitution S643P, which confers resistance to the antifungal drug echinocandin, was located in TM helix 5, where it caused rearrangement of bound lipids. Although the precise mechanism by which S643P renders FKS insensitive to this drug remains to be determined, the structural characterization of this enzyme paves the way to the future design of new antifungal compounds.
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