Molecular dynamics simulations reveal the impact of NUDT15 R139C and R139H variants in structural conformation and dynamics
NUDT15, also known as MTH2, is a member of the NUDIX protein family that catalyzes the hydrolysis of nucleotides and deoxynucleotides, as well as thioguanine analogues. NUDT15 has been reported as a DNA sanitizer in humans, and more recent studies have shown that some genetic variants are related to...
| Autores: | , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Alcalá (UAH) |
| Repositorio: | e_Buah Biblioteca Digital Universidad de Alcalá |
| Idioma: | inglés |
| OAI Identifier: | oai:ebuah.uah.es:10017/60671 |
| Acceso en línea: | http://hdl.handle.net/10017/60671 https://dx.doi.org/10.1080/07391102.2023.2187626 |
| Access Level: | acceso abierto |
| Palabra clave: | NUDT15 MTH2 nudix hydrolase molecular dynamics thiopurine PCA Química Chemistry |
| Sumario: | NUDT15, also known as MTH2, is a member of the NUDIX protein family that catalyzes the hydrolysis of nucleotides and deoxynucleotides, as well as thioguanine analogues. NUDT15 has been reported as a DNA sanitizer in humans, and more recent studies have shown that some genetic variants are related to a poor prognosis in neoplastic and immunologic diseases treated with thioguanine drugs. Despite this, the role of NUDT15 in physiology and molecular biology is quite unclear, as is the mechanism of action of this enzyme. The existence of clinically relevant variants has prompted the study of these enzymes, whose capacity to bind and hydrolyze thioguanine nucleotides is still poorly understood. By using a combination of biomolecular modeling techniques and molecular dynamics, we have studied the monomeric wild type NUDT15 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 ?2 helix affect a network of hydrophobic and ?-interactions that enclose the active site. This knowledge contributes to the understanding of NUDT15 structural dynamics and will be valuable for the design of new chemical probes and drugs targeting this protein. |
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