Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid.
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.
Sintchak
M D
MD
Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139-4211, USA.
Fleming
M A
MA
Futer
O
O
Raybuck
S A
SA
Chambers
S P
SP
Caron
P R
PR
Murcko
M A
MA
Wilson
K P
KP
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
D007166:Immunosuppressive Agents; D007291:Inosine Monophosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D011188:Potassium