Structural analysis of bacterial ABC transporter inhibition by an antibody fragment

Structure
Shivani AhujaChristopher M Koth

Abstract

Bacterial ATP-binding cassette (ABC) importers play critical roles in nutrient acquisition and are potential antibacterial targets. However, structural bases for their inhibition are poorly defined. These pathways typically rely on substrate binding proteins (SBPs), which are essential for substrate recognition, delivery, and transporter function. We report the crystal structure of a Staphylococcus aureus SBP for Mn(II), termed MntC, in complex with FabC1, a potent antibody inhibitor of the MntABC pathway. This pathway is essential and highly expressed during S. aureus infection and facilitates the import of Mn(II), a critical cofactor for enzymes that detoxify reactive oxygen species (ROS). Structure-based functional studies indicate that FabC1 sterically blocks a structurally conserved surface of MntC, preventing its interaction with the MntB membrane importer and increasing wild-type S. aureus sensitivity to oxidative stress by more than 10-fold. The results define an SBP blocking mechanism as the basis for ABC importer inhibition by an engineered antibody fragment.

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Citations

Jun 13, 2015·International Journal of Molecular Sciences·Enrico MalitoMatthew J Bottomley
Jan 4, 2017·Acta Crystallographica. Section F, Structural Biology Communications·Simone CulurgioniMartin Austin Walsh
Sep 4, 2019·Acta Crystallographica. Section D, Structural Biology·Christopher D RadkaStephen G Aller
Nov 1, 2020·Science Advances·Fengjiang LiuZihe Rao
Dec 7, 2021·Acta Crystallographica. Section D, Structural Biology·Suraj Kumar Mandal, Shankar Prasad Kanaujia

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