Cryo-electron microscopy structures of a high-affinity zinc ABC transporter

Zn2+ is an essential micronutrient to all living organisms and plays a key role in various physiological functions. Microorganisms employ high-affinity Zn2+ ABC transporters to uptake zinc from the environment when it is scarce. However, 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. The complex has two ZnuB subunits for transport and two ZnuC subunits for regulation. The ZnuB homodimer is in an outward-facing, closed conformation with a large hydrophilic cavity at the dimer interface. The ZnuC subunits contain an N-terminal ATP-binding cassette (ABC) domain (NBD) and a C-terminal zinc-sensing domain (ZSD). Zn2+ binding to the ZSD locks the transporter in a closed state regardless of nucleotide, whereas under low-Zn2+ conditions, ZSD C-terminal disorder permits ATP-driven zinc uptake. High-affinity zinc ABC transporters are ubiquitously utilized by pathogenic bacteria to evade host immune systems in competing for essential Zn2+. These findings highlight new pharmaceutical targets for disrupting Zn2+ homeostasis in antibiotic-resistant pathogens. One-sentence summaryHigh-affinity zinc ABC transporter structures show a self-regulating mechanism via a built-in zinc sensor.