X-RAY STRUCTURE OF HUMAN FPPS AND USE FOR SELECTING FPPS BINDING COMPOUNDS.

摘要

The present invention relates to crystalline human farnesyl diphosphate synthase (FPPS), to the three-dimensional structure of free FPPS, as well as the three-dimensional structures of FPPS in complex with substrates such as IPP (isopentenyl diphosphate) and/or with inhibitors, such as Zometa???? or Aredia????. Further, methods for preparing crystals of human FPPS are described. According to the invention the crystals can be used to determine the structures of FPPS homologs, mutants, complexes with ligands, FPPS crystal forms and similar molecules of unknown structure. The invention further relates to the use of FPPS crystals to select new FPPS ligands, e.g., by X-ray screening and to design and/or identify inhibitors against FPPS. Furthermore, the invention relates to NMR methods for selecting and/or identifying new low molecular weight binders to FPPS, which represent new therapeutic agents.