STRUCTURE AND MECHANISM OF INOSINE MONOPHOSPHATE DEHYDROGENASE IN COMPLEX WITH THE IMMUNOSUPPRESSANT MYCOPHENOLIC-ACID

The structure of inosine-5'-monophosphate dehydrogenase (IMPDH) in com plex with IMP and mycophenolic acid (MPA) has been determined by X-ray diffraction. IMPDH plays a central role in B and T lymphocyte replica tion. MPA is a potent IMPDH inhibitor and the active metabolite of an immunosuppressive drug recently approved for the treatment of allograf t rejection. IMPDH comprises two domains: a core domain, which is an a lpha/beta barrel and contains the active site, and a flanking domain. The complex, in combination with mutagenesis and kinetic data, provide s a structural basis for understanding the mechanism of IMPDH activity and indicates that MPA inhibits IMPDH by acting as a replacement for the nicotinamide portion of the nicotinamide adenine dinucleotide cofa ctor and a catalytic water molecule.