Abstract
AbstractNUDT15 or MTH2 is a member of NUDIX protein family that catalyze the hydrolysis of nucleotides and deoxynucleotides, including thioguanine analogues. NUTD15 has been reported as a DNA sanitizer in humans, and more recent studies have proved that genomic variants are related to a poor prognosis in inmoplastic and immunologic diseases with thioguanines. Despite of this, the role of NUTD15 in physiology and molecular biology is quite unclear, as well as the mechanism of action of this enzyme. The existence of clinically relevant variants has prompted the study of this enzymes, whose capacity to bound and hydrolyze thioguanine nucleotides is still poor understood. By using a combination of biomolecular modelling techniques together with molecular dynamics we have studied the monomeric wild type NUTD15, as well as two important variants R139C and R139H. Our findings reveal not only how nucleotide binding stabilizes the enzyme, but also how two loops are responsible for keeping the enzyme in a packed close conformation. Mutations in α2 helix affect a network of hydrophobic and π-interactions that are responsible of active site enclosing.
Publisher
Cold Spring Harbor Laboratory