Skip to main content
SLU publication database (SLUpub)

Research article2011Peer reviewedOpen access

Cofactor mobility determines reaction outcome in the IMPDH and GMPR (beta-alpha)(8) barrel enzymes

Patton, GC; Stenmark, P; Gollapalli, DR; Sevastik, R; Kursula, P; Flodin, S; Schuler, H; Swales, CT; Eklund, Hans; Himo, F; Nordlund, P; Hedström, L


Inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate reductase (GMPR) belong to the same structural family, share a common set of catalytic residues and bind the same ligands. The structural and mechanistic features that determine reaction outcome in the IMPDH and GMPR family have not been identified. Here we show that the GMPR reaction uses the same intermediate E-XMP star as IMPDH, but in this reaction the intermediate reacts with ammonia instead of water. A single crystal structure of human GMPR type 2 with IMP and NADPH fortuitously captures three different states, each of which mimics a distinct step in the catalytic cycle of GMPR. The cofactor is found in two conformations: an 'in' conformation poised for hydride transfer and an 'out' conformation in which the cofactor is 6 angstrom from IMP. Mutagenesis along with substrate and cofactor analog experiments demonstrate that the out conformation is required for the deamination of GMP. Remarkably, the cofactor is part of the catalytic machinery that activates ammonia.

Published in

Cell Chemistry and Biology
2011, Volume: 7, number: 12, pages: 950-958

      SLU Authors

    • Eklund, Hans

      • Department of Molecular Biology, Swedish University of Agricultural Sciences

    UKÄ Subject classification

    Biochemistry and Molecular Biology

    Publication identifier


    Permanent link to this page (URI)