Abstract
Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB) and has evolved an incredible ability to survive latently within the human host for decades. The Mtb pathogen encodes for a low number of ATP-binding cassette (ABC) importers for the acquisition of carbohydrates that may reflect the nutrient poor environment within the host macrophages. Mtb UgpB (Rv2833c) is the substrate binding domain of the UgpABCE transporter that recognizes glycerophosphocholine (GPC), indicating that this transporter has a role in recycling glycerophospholipid metabolites. By using a combination of saturation transfer difference (STD) NMR and X-ray crystallography, we report the structural analysis of Mtb UgpB complexed with GPC and have identified that Mtb UgpB not only recognizes GPC but is also promiscuous for a broad range of glycerophosphodiesters. Complementary biochemical analyses and site-directed mutagenesis precisely define the molecular basis and specificity of glycerophosphodiester recognition. Our results provide critical insights into the structural and functional role of the Mtb UgpB transporter and reveal that the specificity of this ABC-transporter is not limited to GPC, therefore optimizing the ability of Mtb to scavenge scarce nutrients and essential glycerophospholipid metabolites via a single transporter during intracellular infection.
Highlights
Bacterial pathogens have evolved a wide range of strategies to survive and thrive within their host environment
The sugars that are available within the nutrient-limited macrophage environment are unknown; Mycobacterium tuberculosis (Mtb) is equipped with five putative importers of carbohydrate substrates: four members of the ATP-binding cassette (ABC) transporter family and one belonging to the major facilitator superfamily.[3,4]
To overcome this, we chemically modified the surface of Mtb UgpB through reductive methylation, and this resulted in crystals of UgpB in complex with GPC
Summary
Bacterial pathogens have evolved a wide range of strategies to survive and thrive within their host environment. We report the first crystal structure of Mtb UgpB in complex with GPC and identify, in both solid and solution state, the molecular determinants of binding and critical features for glycerophosphodiester recognition.
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