5GVX

Structural insight into dephosphorylation by Trehalose 6-phosphate Phosphatase (OtsB2) from Mycobacterium Tuberculosis

Summary for 5GVX

• Entry DOI: 10.2210/pdb5gvx/pdb
• Descriptor: Trehalose-phosphate phosphatase, MAGNESIUM ION (3 entities in total)
• Functional Keywords: mtbtpp, trehalose, phosphatase, drug discovery, hydrolase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 45973.16

Authors

Shan, S.,Min, H.,Liu, T.,Jiang, D.,Rao, Z. (deposition date: 2016-09-07, release date: 2017-09-27, Last modification date: 2024-03-20)

Primary citation

Shan, S.,Min, H.,Liu, T.,Jiang, D.,Rao, Z.
Structural insight into dephosphorylation by trehalose 6-phosphate phosphatase (OtsB2) from Mycobacterium tuberculosis.
FASEB J., 30:3989-3996, 2016

PubMed Abstract: Trehalose serves as a key structural component in the cell wall of Mycobacterium tuberculosis. M. tuberculosis trehalose-6-phosphate phosphatase (MtbTPP), an essential enzyme in the trehalose biosynthesis OtsAB pathway, catalyzes the dephosphorylation of trehalose-6-phosphate (trehalose-6-P) to generate trehalose, and plays a critical role in M. tuberculosis survival-associated cell wall formation and permeability. Therefore, MtbTPP (OtsB2) is considered a promising potential target for discovery of antimicrobial drugs. However, the absence of structural information of MtbTPP restrains our understanding of its underlying catalytic mechanism. Here, we report the high-resolution crystal structures of apo active MtbTPP and its trehalose-6-P bound complex. The apo structure presents a canonical haloacid dehalogenase superfamily structural fold plus an extra N-terminal domain. The catalytic center is located in a positively charged cleft between the hydrolase domain and the cap domain, demonstrating a highly conserved substrate binding pocket. The role of residues interacting with the substrate in catalysis were probed by site-directed mutagenesis. Asp147, Asp149, Asp330, and Asp331 were found to be pivotal for the enzymatic activity of MtbTPP. The MtbTPP structures reported here provide insight into a key step in the biosynthesis of trehalose, which would facilitate future development of anti-TB therapeutics.-Shan, S., Min, H., Liu, T., Jiang, D., Rao, Z. Structural insight into dephosphorylation by trehalose 6-phosphate phosphatase (OtsB2) from Mycobacterium tuberculosis.

PubMed: 27572957
DOI: 10.1096/fj.201600463R

Experimental method

X-RAY DIFFRACTION (2.596 Å)