title: Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid.
abstract: The structure of inosine-5'-monophosphate dehydrogenase (IMPDH) in complex with IMP and mycophenolic acid (MPA) has been determined by X-ray diffraction. IMPDH plays a central role in B and T lymphocyte replication. MPA is a potent IMPDH inhibitor and the active metabolite of an immunosuppressive drug recently approved for the treatment of allograft rejection. IMPDH comprises two domains: a core domain, which is an alpha/beta barrel and contains the active site, and a flanking domain. The complex, in combination with mutagenesis and kinetic data, provides 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 cofactor and a catalytic water molecule.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139-4211, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Sintchak
authors.forename: M A
authors.initials: MA
authors.lastname: Fleming
authors.forename: O
authors.initials: O
authors.lastname: Futer
authors.forename: S A
authors.initials: SA
authors.lastname: Raybuck
authors.forename: S P
authors.initials: SP
authors.lastname: Chambers
authors.forename: P R
authors.initials: PR
authors.lastname: Caron
authors.forename: M A
authors.initials: MA
authors.lastname: Murcko
authors.forename: K P
authors.initials: KP
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001665:Binding Sites; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000378:metabolism*; D007291:Inosine Monophosphate / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D007166:Immunosuppressive Agents; D007291:Inosine Monophosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D011188:Potassium