Premium
Studying dynamics without explicit dynamics: A structure‐based study of the export mechanism by AcrB
Author(s) -
Simsir Méliné,
Broutin Isabelle,
MusVeteau Isabelle,
Cazals Frédéric
Publication year - 2021
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.26012
Subject(s) - trimer , efflux , mechanism (biology) , allosteric regulation , molecular dynamics , computational biology , transmembrane protein , multidrug resistance associated proteins , protein structure , biology , chemistry , biophysics , biochemistry , transporter , dimer , atp binding cassette transporter , physics , enzyme , gene , computational chemistry , receptor , organic chemistry , quantum mechanics
Resistance‐nodulation‐cell division family proteins are transmembrane proteins identified as large spectrum drug transporters involved in multidrug resistance. A prototypical case in this superfamily, responsible for antibiotic resistance in selected gram‐negative bacteria, is AcrB. AcrB forms a trimer using the proton motive force to efflux drugs, implementing a functional rotation mechanism. Unfortunately, the size of the system (1049 amino acid per monomer and membrane) has prevented a systematic dynamical exploration, so that the mild understanding of this coupled transport jeopardizes our ability to counter it. The large number of crystal structures of AcrB prompts studies to further our understanding of the mechanism. To this end, we present a novel strategy based on two key ingredients, which are to study dynamics by exploiting information embodied in the numerous crystal structures obtained to date, and to systematically consider subdomains, their dynamics, and their interactions. Along the way, we identify the subdomains responsible for dynamic events, refine the states (A, B, E) of the functional rotation mechanism, and analyze the evolution of intramonomer and intermonomer interfaces along the functional cycle. Our analysis shows the relevance of AcrB's efflux mechanism as a template within the HAE1 family but not beyond. It also paves the way to targeted simulations exploiting the most relevant degrees of freedom at certain steps, and to a targeting of specific interfaces to block the drug efflux. Our work shows that complex dynamics can be unveiled from static snapshots, a strategy that may be used on a variety of molecular machines of large size.