Sammanfattning

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.

Publicerad i

Cell Chemistry and Biology
2011, Volym: 7, nummer: 12, sidor: 950-958
Utgivare: NATURE PUBLISHING GROUP

SLU författare

• Eklund, Hans

  • Institutionen för molekylärbiologi, Sveriges lantbruksuniversitet
    

UKÄ forskningsämne

Biokemi och molekylärbiologi


Publikationens identifierare

DOI: https://doi.org/10.1038/NCHEMBIO.693

Permanent länk till denna sida (URI)

https://res.slu.se/id/publ/46106