PDBsum entry 6b5e

Transferase

PDB id: 6b5e

Contents

Protein chains

(+ 2 more) 283 a.a.

Ligands

DAU ×10

TYD ×6

EDO

Metals

_NA ×2

_MG ×9

_CL

Waters ×1477

References listed in PDB file

Key reference

• Title: The structure of glucose-1-Phosphate thymidylyltransferase from mycobacterium tuberculosis reveals the location of an essential magnesium ion in the rmla-Type enzymes.
• Authors: H.A.Brown, J.B.Thoden, P.A.Tipton, H.M.Holden.
• Ref.: Protein Sci, 2018, 27, 441-450.
• PubMed id: 29076563

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.