RT Journal Article SR Electronic T1 Mycobacterial OtsA structures unveil substrate preference mechanism and allosteric regulation by 2-oxoglutarate and 2-phosphoglycerate JF bioRxiv FD Cold Spring Harbor Laboratory SP 677302 DO 10.1101/677302 A1 Vítor Mendes A1 Marta Acebrón-García-de-Eulate A1 Nupur Verma A1 Michal Blaszczyk A1 Márcio V. B. Dias A1 Tom L. Blundell YR 2019 UL http://biorxiv.org/content/early/2019/07/05/677302.abstract AB Trehalose is an essential disaccharide for mycobacteria and a key constituent of several cell wall glycolipids with fundamental roles in pathogenesis. Mycobacteria possess two pathways for trehalose biosynthesis. However, only the OtsAB pathway was found to be essential in M. tuberculosis, with marked growth and virulence defects of OtsA mutants and strict essentiality of OtsB2. Herein, we report the first mycobacterial OtsA structures from M. thermoresistibile in both apo and ligand-bound forms. Structural information reveals three key residues in the mechanism of substrate preference that were further confirmed by site-directed mutagenesis. Additionally, we identify 2-oxoglutarate and 2-phosphoglycerate as allosteric regulators of OtsA. The structural analysis in this work strongly contributed to define the mechanisms for feedback inhibition, show different conformational states of the enzyme and map a new allosteric site.