STRUCTURAL BASIS FOR MULTIPLE LIGAND SPECIFICITY OF THE PERIPLASMIC LYSINE, ARGININE, ORNITHINE-BINDING PROTEIN

The substrate-binding site of a protein with multiple specificity shou ld satisfy geometric and energetic complementarity for several differe nt substrates. The structural basis of the multiple ligand specificity of the periplasmic lysine-, arginine-, ornithine-binding protein (LAO ) was investigated by determining and analyzing the structures of the protein unliganded and liganded with each of the three high-affinity l igands (L-lysine, L-arginine, and L-ornithine) and with one low-affini ty ligand (L-histidine). The geometric complementarity is achieved pri marily by virtue of the large size of the ligand-binding site which ca n accommodate the maximum common volume of the four ligands plus three water molecules. The optimization of energetic complementarity is ach ieved by the relocation of protein-bound water molecules and by the mo vement of the Asp-11 side chain. The structure of the LAO-histidine co mplex indicates that the 30-fold reduced affinity of the protein for h istidine is primarily due to unavailability of one ionic interaction o f the histidine side chain with the protein which is present in the ot her three complexes.