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bioRxiv · 10.1101/2020.10.21.349639

Structural basis of inhibition of a putative drug efflux transporter NorC, through a single-domain camelid antibody

Kumar, S.·Athreya, A.·Gulati, A.·Nair, R. M.·Penmatsa, A.
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Abstract

Multi-drug efflux is a major mechanism of acquiring antimicrobial resistance among superbugs. In this study, we report the X-ray structure of NorC, a 14 transmembrane major facilitator superfamily member that is implicated in fluoroquinolone resistance in drug-resistant Staphylococcus aureus strains, at a resolution of 3.6 [A]. The NorC structure was determined in complex with a single-domain camelid antibody that interacts at the extracellular face of the transporter and stabilizes it in an outward-open conformation. The complementarity determining regions of the antibody enter and block solvent access to the interior of the vestibule, thereby inhibiting alternating-access. NorC specifically interacts with an organic cation, tetraphenylphosphonium, although it does not demonstrate an ability to transport it. The interaction is compromised in the presence of NorC-antibody complex, consequently establishing a strategy to detect and block NorC and related efflux pumps through the use of single- domain camelid antibodies.

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Kumar, S., Athreya, A., Gulati, A., Nair, R. M., Penmatsa, A.. 2020-10-22. Structural basis of inhibition of a putative drug efflux transporter NorC, through a single-domain camelid antibody. https://doi.org/10.1101/2020.10.21.349639

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