Coordination promiscuity guarantees metal substrate selection in transmembrane primary-active Zn²⁺ pumps

Metal selectivity in P_1B-type ATPase pumps appears to be determined by amino acid motifs on their transmembrane helices. We reveal the principles governing substrate promiscuity towards first-, second- and third-row transition metals in a transmembrane Zn²⁺/Cd²⁺/Hg²⁺/Pb²⁺ P-type ATPase (ZntA), by dissecting its coordination chemistry. Atomic resolution characterization in detergent micelles and lipid bilayers reveals a "plastic" transmembrane metal-binding site that selects substrates by unique and diverse, yet defined, coordination geometries and ligand-metal distances.