Abstract
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 3.0 Å 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 Cys186 is the potential active site, and that the conformation of the loop (residues 129-133) suggests a preference for the coenzyme NADPH over NADH. This structure provides important information towards understanding the functions of members of the GMPR family.
Original language | English (US) |
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Pages (from-to) | 980-988 |
Number of pages | 9 |
Journal | Journal of Molecular Biology |
Volume | 355 |
Issue number | 5 |
DOIs | |
State | Published - Feb 3 2006 |
Keywords
- Crystal structure
- GMP
- Guanosine monophosphate reductase 2
- Purine salvage
ASJC Scopus subject areas
- Structural Biology
- Molecular Biology