Structural studies and tissue distribution of human GCPII and characterization of its rat and porcine orthologs

Abstract

Since GCPII is a potential pharmacological target, it is being extensively snrdied in many labs all around the world and these studies comprise many topics. This is minored also by this PhD thesis. The papers included here concem two major issues: 1. analysis ofGCPII structure and interactions with ligands; 2. study of CCPII distribution in tissues of human and two other species considered as potential animal models and kinetic characterization of the corresponding GCPII orthologs. Structural studies of GCPII active site and substrate binding are driven by the attempt to broaden the information that could help the rational design of novel small GCPII ligands, functioning either as inhibitors in neuronal damage or as imaging agents in cancer diagnosis. Two papers included in this thesis describe ligand binding in the GCPII active site in detail, with particular ernphasis on the Sl'pocket in one case and on the Sl pocket in the other' Based on our findings, we can describe a set of interactions goveming GCPII affinity to a substrate, accommodations that CCPII active site is capable of during ligand binding, the limits imposed on the ligand and tolerance of the enzyme to varying ligand nature. All these pieces of infomation are useful for the design of novel compounds with high affinity to GCPII' sufÍicient...