The catalytic activity of malic enzyme (ME), a member of a new class of oxidative decarboxylases, requires the presence of divalent cations (Mn2+, Mg2+, and others). The crystal structure at 2.9 Angstrom resolution of human mitochondrial NAD(+)-dependent malic enzyme in a ternary complex with NAD(+) and the lanthanide ion Lu3+, Which has similar radius as Mn2+, reveals a new conformation of the enzyme. The active site in this ternary complex is in an open form, while the organization of the tetramer of the enzyme actually resembles that with a closed active site. The Lu3+ ion is bound to the enzyme at the same site as Mn2+. Kinetic studies showed that Lu3+ is a potent inhibitor of both the human NAD(P)(+)-dependent ME and the NADP(+)-dependent ME from pigeon liver, and is competitive with respect to the divalent cation, consistent with the structural information.