New insight into the architecture of oxy-anion pocket in unliganded conformation of GAT domains: A MD-simulation study

Human Guanine Monophosphate Synthetase (hGMPS) converts XMP to GMP, and acts as a bifunctional enzyme with N-terminal ``glutaminase'' (GAT) and C-terminal ``synthetase'' domain. The enzyme is identified as a potential target for anticancer and immunosuppressive therapies. GAT domain of enzyme plays central role in metabolism, and contains conserved catalytic residues Cys104, His190, and Glu192. MD simulation studies on GAT domain suggest that position of oxyanion in unliganded conformation is occupied by one conserved water molecule (W1), which also stabilizes that pocket. This position is occupied by a negatively charged atom of the substrate or ligand in ligand bound crystal structures. In fact, MD simulation study of Ser75 to Val indicates that W1 conserved water molecule is stabilized by Ser75, while Thr152, and His190 also act as anchor residues to maintain appropriate architecture of oxyanion pocket through water mediated H-bond interactions. Possibly, four conserved water molecules stabilize oxyanion hole in unliganded state, but they vacate these positions when the enzyme (hGMPS)-substrate complex is formed. Thus this study not only reveals functionally important role of conserved water molecules in GAT domain, but also highlights essential role of other non-catalytic residues such as Ser75 and Thr152 in this enzymatic domain. The results from this computational study could be of interest to experimental community and provide a testable hypothesis for experimental validation. Conserved sites of water molecules near and at oxyanion hole highlight structural importance of water molecules and suggest a rethink of the conventional definition of chemical geometry of inhibitor binding site.

Guiron le Courtois, translaté de latin en françois par Luce du Châtel du Gat.

Commencement : « O Dieu qui m'a donné povoir et engin... » — Fin : « ...et retourne au roy Melyadus pour compter partie de ses aventures. — Cy fine le premier livre Guyron le Courtoys. »

Guiron le Courtois, translaté de latin en françois par Luce du Châtel du Gat. « Cy commence li seconds livres de Guiron le Courtois »

Commencement : « Or dist li contes que li rois Melyadus demoura ou chastel... » — Fin : « ...et encore est communement son nom par toute Engleterre. — Cy fine le tiers et derrenier livre de Guiron le Courtois. »

Donar gat per llebre (o la impostura a l'ensenyament). 'Dar gato por liebre (o la impostura en la enseñanza)'.

Reflexión entorno a las apariencias. Se parte de la idea de que vivimos en una sociedad que promueve las apariencias: política, medios de comunicación o querer caer bien a los demás pueden ser algunos ejemplos. Esto puede crear preocupaciones en los adolescentes que se encuentran en pleno desarrollo físico y psicológico. Plantea ideas para contrarrestar este fenómeno y ayudar al alumnado a desarrollarse tal como es.