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

Metal selectivity in P1B-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.