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Guanosine monophosphate reductase (GMPR) catalyzes the irreversible and NADPH-dependent reductive deamination of GMP to IMP, and plays a critical role in re-utilization of free intracellular bases and purine nucleosides. Here, we report the first crystal structure of human GMP reducatase 2 (hGMPR2) in complex with GMP at 3.0Å resolution. The protein forms a tetramer composed of subunits adopting the ubiquitous (α/β)₈ barrel fold. Interestingly, the substrate GMP is bound to hGMPR2 through interactions with Met269, Ser270, Arg286, Ser288, and Gly290; this makes the conformation of the adjacent flexible binding region (residues 268–289) fixed, much like a door on a hinge. Structure comparison and sequence alignment analyses show that the conformation of the active site loop (residues 179–187) is similar to those of hGMPR1 and inosine monophosphate dehydrogenases (IMPDHs). We propose that …