L-Proline is an amino acid that plays an important role in proteins uniquely contributing to protein folding, structure, and stability, and this amino acid serves as a sequence-recognition motif. Proline biosynthesis can occur via two pathways, one from glutamate and the other from arginine. In both pathways, the last step of biosynthesis, the conversion of Δ 1 -pyrroline-5-carboxylate (P5C) to Lproline, is catalyzed by Δ 1 -pyrroline-5-carboxylate reductase (P5CR) using NAD(P)H as a cofactor. We have determined the first crystal structure of P5CR from two human pathogens, Neisseria meningitides and Streptococcus pyogenes, at 2.0Å and 2.15Å resolution, respectively. The catalytic unit of P5CR is a dimer composed of two domains, but the biological unit seems to be speciesspecific. The N-terminal domain of P5CR is an α/β/α sandwich, a Rossmann fold. The C-terminal dimerization domain is rich in α-helices and shows domain swapping. Comparison of the native structure of P5CR to structures complexed with L-proline and NADP + in two quite different primary sequence backgrounds provides unique information about key functional features: the active site and the catalytic mechanism. The inhibitory L-proline has been observed in the crystal structure.

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