6B5K

Mycobacterium tuberculosis RmlA in complex with Mg/dTTP

Summary for 6B5K

• Entry DOI: 10.2210/pdb6b5k/pdb
• Descriptor: Glucose-1-phosphate thymidylyltransferase, THYMIDINE-5'-TRIPHOSPHATE, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: nucleotidyltransferase, transferase, substrate, sugar-modifying
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 2
• Total formula weight: 67112.08

Authors

Brown, H.A.,Holden, H.A. (deposition date: 2017-09-29, release date: 2018-02-21, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.6 Å)