5L3K

Structure of Mycobacterium thermoresistibile trehalose-6-phosphate synthase in a ternary complex with ADP and fructose-6-phosphate

Summary for 5L3K

• Entry DOI: 10.2210/pdb5l3k/pdb
• Descriptor: Alpha,alpha-trehalose-phosphate synthase, ADENOSINE-5'-DIPHOSPHATE, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: otsa, trehalose-6-phosphate synthase, trehalose, transferase
• Biological source: Mycobacterium thermoresistibile
• Total number of polymer chains: 8
• Total formula weight: 442922.69

Authors

Mendes, V.,Verma, N.,Blaszczyk, M.,Blundell, T.L. (deposition date: 2016-05-23, release date: 2017-06-07, Last modification date: 2024-01-10)

Primary citation

Mendes, V.,Acebron-Garcia-de-Eulate, M.,Verma, N.,Blaszczyk, M.,Dias, M.V.B.,Blundell, T.L.
Mycobacterial OtsA Structures Unveil Substrate Preference Mechanism and Allosteric Regulation by 2-Oxoglutarate and 2-Phosphoglycerate.
Mbio, 10:-, 2019

PubMed Abstract: 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 , with marked growth and virulence defects of OtsA mutants and strict essentiality of OtsB2. Here, we report the first mycobacterial OtsA structures from 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. Mycobacterial infections are a significant source of mortality worldwide, causing millions of deaths annually. Trehalose is a multipurpose disaccharide that plays a fundamental structural role in these organisms as a component of mycolic acids, a molecular hallmark of the cell envelope of mycobacteria. Here, we describe the first mycobacterial OtsA structures. We show mechanisms of substrate preference and show that OtsA is regulated allosterically by 2-oxoglutarate and 2-phosphoglycerate at an interfacial site. These results identify a new allosteric site and provide insight on the regulation of trehalose synthesis through the OtsAB pathway in mycobacteria.

PubMed: 31772052
DOI: 10.1128/mBio.02272-19

Experimental method

X-RAY DIFFRACTION (2.305 Å)