Cryo-electron microscopy structure of a zinc uptake ABC transporter

Zn²⁺ is an essential micronutrient required for many biological processes. Microorganisms employ high-affinity Zn²⁺ ABC transporters to take up zinc from the environment when it is scarce, yet the mechanism of zinc uptake and its regulation remain poorly understood. Here, we report the cryo-electron microscopy structure of the Zn²⁺ ABC transporter complex ZnuB-ZnuC from Escherichia coli. It contains two ZnuB transport subunits and two ZnuC regulatory subunits. The ZnuB homodimer is in an outward-facing, closed conformation with a large hydrophilic cavity at the dimer interface. Each ZnuC subunit contains an N-terminal nucleotide-binding domain and a C-terminal zinc-sensing domain (ZSD). Zn²⁺ binding to the ZSD locks the transporter in a closed state, whereas under low-Zn²⁺ conditions, the disorder of ZSD permits ATP-driven zinc uptake. Zn²⁺ ABC transporters are ubiquitously utilized by pathogenic bacteria to compete with hosts for Zn²⁺. These findings reveal potential therapeutic targets for disrupting Zn²⁺ homeostasis in antibiotic-resistant pathogens.