NADP(+) dependent isocitrate dehydrogenase (IDH; EC 184.108.40.206) belongs to a large family of alpha-hydroxyacid oxidative beta-decarboxylases that catalyze similar three-step reactions, with dehydrogenation to an oxaloacid intermediate preceding beta-decarboxylation to an enol intermediate followed by tautomerization to the final alpha-ketone product. A comprehensive view of the induced fit needed for catalysis is revealed on comparing the first "fully closed" crystal structures of a pseudo-Michaelis complex of wild-type Escherichia coli IDH (EcoIDH) and the "fully closed" reaction product complex of the K100M mutant with previously obtained "quasi-closed" and "open" conformations. Conserved catalytic residues, binding the nicotinamide ring of NADP(+) and the metal-bound substrate, move as rigid bodies during domain closure by a hinge motion that spans the central beta-sheet in each monomer. Interactions established between Thr105 and Ser113, which flank the "phosphorylation loop", and the nicotinamide mononucleotide moiety of NADP(+) establish productive coenzyme binding. Electrostatic interactions of a Lys100-Leu103-Asn115-Glu336 tetrad play a pivotal role in assembling a catalytically competent active site. As predicted, Lys230* is positioned to deprotonate/reprotonate the alpha-hydroxyl in both reaction steps and Tyr160 moves into position to protonate C3 following beta-decarboxylation. A proton relay from the catalytic triad Tyr160-Asp307-Lys230* connects the alpha-hydroxyl of isocitrate to the bulk solvent to complete the picture of the catalytic mechanism.