Premium
Modeling the Transport Mechanism of MsbA and P‐glycoprotein
Author(s) -
Hills Ronald,
Black Cody
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01764
Subject(s) - atp binding cassette transporter , efflux , chemistry , transmembrane protein , transmembrane domain , p glycoprotein , plasma protein binding , transporter , transport protein , biochemistry , multiple drug resistance , ligand (biochemistry) , microbiology and biotechnology , biology , membrane , gene , antibiotics , receptor
MsbA and P‐glycoprotein (P‐gp) are structurally, functionally, and mechanistically similar ABC transporter proteins. MsbA is found in gram‐negative bacteria, while P‐gp is found in intestinal and blood‐brain membranes. The endogenous substrate for MsbA is membrane component lipopolysaccharide (LPS), whereas P‐gp exports foreign xenobiotics, being responsible for drug efflux activity in acquired multidrug resistance to chemotherapeutics. Co‐crystal structures have been determined for P‐gp with bound ligand, but MsbA has yet to be solved in the presence of inhibitors or LPS. Elucidating the chemical characteristics of substrates and their protein binding pockets provides insight for designing inhibitors to combat drug resistance. We constructed three‐dimensional models at key points along the LPS translocation pathway. A mechanism for transport is revealed involving clusters of basic arginine residues at the entry and exit portions of the transmembrane chamber. Lastly, sequence and structural analysis of P‐gp revealed the location of putative cholesterol binding sites that are likely to influence drug transport.