We demonstrate how tryptophanyl-tRNA synthetase uses conformation-dependent Mg 2+ activation to couple catalysis of tryptophan activation to specific, functional domain movements. Rate acceleration by Mg 2+ requires ∼−6.0 kcal/mol in protein⋅Mg 2+ interaction energy, none of which arises from the active site. A highly cooperative interaction between Mg 2+ and four residues from a remote, conserved motif that mediates the shear of domain movement (1) destabilizes the pretransition state conformation, thereby (2) inducing the Mg 2+ to stabilize the transition state for k cat by ∼−5.0 kcal/mol. Cooperative, long-range conformational effects on the metal therefore convert an inactive Mg 2+ coordination into one that can stabilize the transition state if, and only if, domain motion occurs. Transient, conformation-dependent Mg 2+ activation, analogous to the escapement in mechanical clocks, explains vectorial coupling.