Download MendeleyStructural Basis for the Specificity of Human Nudt16 and its Regulation by Inosine Monophosphate.
Tresaugues, L., Lundback, T., Welin, M., Flodin, S., Nyman, T., Silvander, C., Graslund, S., Nordlund, P.(2015) PLoS One 10: 31507
- PubMed: 26121039
- DOI: https://doi.org/10.1371/journal.pone.0131507
- Primary Citation of Related Structures:
2XSQ - PubMed Abstract:
Human NUDT16 is a member of the NUDIX hydrolase superfamily. After having been initially described as an mRNA decapping enzyme, recent studies conferred it a role as an "housecleaning" enzyme specialized in the removal of hazardous (deoxy)inosine diphosphate from the nucleotide pool. Here we present the crystal structure of human NUDT16 both in its apo-form and in complex with its product inosine monophosphate (IMP). NUDT16 appears as a dimer whose formation generates a positively charged trench to accommodate substrate-binding. Complementation of the structural data with detailed enzymatic and biophysical studies revealed the determinants of substrate recognition and particularly the importance of the substituents in position 2 and 6 on the purine ring. The affinity for the IMP product, harboring a carbonyl in position 6 on the base, compared to purine monophosphates lacking a H-bond acceptor in this position, implies a catalytic cycle whose rate is primarily regulated by the product-release step. Finally, we have also characterized a phenomenon of inhibition by the product of the reaction, IMP, which might exclude non-deleterious nucleotides from NUDT16-mediated hydrolysis regardless of their cellular concentration. Taken together, this study details structural and regulatory mechanisms explaining how substrates are selected for hydrolysis by human NUDT16.
Organizational Affiliation:
Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
