Structure and inhibition mechanisms of <i>Mycobacterium tuberculosis</i> essential transporter efflux protein A.

ABSTRACT: A broad chemical genetics screen in Mycobacterium tuberculosis (Mtb) to identify inhibitors of established or previously untapped targets for therapeutic development yielded compounds (BRD-8000.3 and BRD-9327) that inhibit the essential efflux pump EfpA. To understand the mechanisms of inhibition by these compounds, we determined the structures of EfpA with inhibitors bound at 2.7 - 3.4 Å resolution. Our structures reveal different mechanisms of inhibition for the two inhibitors. BRD-8000.3 binds in a tunnel making contact with the lipid bilayer and extending toward the central cavity to displace the fatty acid chain of a lipid molecule bound in the apo structure, suggesting its blocking of an access route for a natural lipidic substrate, in contrast to its uncompetitive mechanism f

SUBMITTER: Khandelwal NK 

PROVIDER: S-EPMC11398473 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature