A finely balanced order-disorder equilibrium sculpts the folding-binding landscape of an antibiotic sequestering protein.

ABSTRACT: TipA, a MerR family transcription factor from Streptomyces lividans, promotes antibiotic resistance by sequestering broad-spectrum thiopeptide-based antibiotics, thus counteracting their inhibitory effect on ribosomes. TipAS, a minimal binding motif which is expressed as an isoform of TipA, harbors a partially disordered N-terminal subdomain that folds upon binding multiple antibiotics. The extent and nature of the underlying molecular heterogeneity in TipAS that shapes its promiscuous folding-function landscape is an open question and is critical for understanding antibiotic-sequestration mechanisms. Here, combining equilibrium and time-resolved experiments, statistical modeling, and simulations, we show that the TipAS native ensemble exhibits a pre-equilibrium between binding-inco

SUBMITTER: Natarajan L 

PROVIDER: S-EPMC11098121 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature