The multidrug transporter Pdr5 from Saccharomyces cerevisiae is an ergosterol-modulated efflux pump

Cryo-EM at 2.2 [A] resolution shows Saccharomyces cerevisiae Pdr5 binds ergosterol in defined grooves and unexpected locations, linking membrane sterol composition to transporter function.

• Why it matters: Multidrug resistance in fungi depends on Pdr5, yet how ergosterol in the plasma membrane tunes its activity remains unclear.
• What they did: The authors determined a cryo-EM structure of Pdr5 with ATP/ADP, assigned ergosterol densities and quantified ergosterol by GC-MS, and identified M(IP)2C by native MS; they also measured activity across ergosterol concentrations and used mutational analysis.
• The result: Pdr5 activity follows a Gaussian-like dependence on ergosterol concentration, with no such modulation in the presence of cholesterol, and mutations support a single ergosterol-binding site that couples a protein–lipid network to the substrate-binding region.

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