6B5E

Mycobacterium tuberculosis RmlA in complex with dTDP-glucose

6B5E の概要

• エントリーDOI: 10.2210/pdb6b5e/pdb
• 分子名称: Glucose-1-phosphate thymidylyltransferase, 2'DEOXY-THYMIDINE-5'-DIPHOSPHO-ALPHA-D-GLUCOSE, MAGNESIUM ION, ... (8 entities in total)
• 機能のキーワード: nucleotidyltransferase, transferase, product, sugar-modifying
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 269154.98

構造登録者

Brown, H.A.,Holden, H.M. (登録日: 2017-09-29, 公開日: 2018-02-21, 最終更新日: 2023-10-04)

主引用文献

Brown, H.A.,Thoden, J.B.,Tipton, P.A.,Holden, H.M.
The structure of glucose-1-phosphate thymidylyltransferase from Mycobacterium tuberculosis reveals the location of an essential magnesium ion in the RmlA-type enzymes.
Protein Sci., 27:441-450, 2018

PubMed Abstract: Tuberculosis, caused by the bacterium Mycobacterium tuberculosis, continues to be a major threat to populations worldwide. Whereas the disease is treatable, the drug regimen is arduous at best with the use of four antimicrobials over a six-month period. There is clearly a pressing need for the development of new therapeutics. One potential target for structure-based drug design is the enzyme RmlA, a glucose-1-phosphate thymidylyltransferase. This enzyme catalyzes the first step in the biosynthesis of l-rhamnose, which is a deoxysugar critical for the integrity of the bacterium's cell wall. Here, we report the X-ray structures of M. tuberculosis RmlA in complex with either dTTP or dTDP-glucose to 1.6 Å and 1.85 Å resolution, respectively. In the RmlA/dTTP complex, two magnesium ions were observed binding to the nucleotide, both ligated in octahedral coordination spheres. In the RmlA/dTDP-glucose complex, only a single magnesium ion was observed. Importantly, for RmlA-type enzymes with known three-dimensional structures, not one model shows the position of the magnesium ion bound to the nucleotide-linked sugar. As such, this investigation represents the first direct observation of the manner in which a magnesium ion is coordinated to the RmlA product and thus has important ramifications for structure-based drug design. In the past, molecular modeling procedures have been employed to derive a three-dimensional model of the M. tuberculosis RmlA for drug design. The X-ray structures presented herein provide a superior molecular scaffold for such endeavors in the treatment of one of the world's deadliest diseases.

PubMed: 29076563
DOI: 10.1002/pro.3333

実験手法

X-RAY DIFFRACTION (1.85 Å)