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From Proteopedia

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Bacterial Multidrug Efflux Transporter AcrB (1IWG)

Efflux pump systems have evolved in bacteria to act as a chemotherapeutic drug and antibiotic resistance mechanism within the bacterial cytoplasmic membrane. These pump systems typically consist of multiple proteins that are embedded in the membranes and periplasms of the bacterial cells, which all bond together to work to recognize and export foreign materials that have come in contact with the cell. They also play an essential role in biofilm formation of capable bacteria, and work to help provide protection and reduce the stress placed on the biofilm core.

1IWG is one component of a three-part AcrAB-TolC multidrug efflux pump system found in E. coli that works to maintain resistance against a range of antibiotics. This protein, which is also called the bacterial multidrug efflux transporter AcrB

spinqualitylabelsall models Basic structure of AcrB protein Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

protein, works together with the AcrA and TolC proteins to capture and export any antibacterial compounds and detergents that can compromise the cell. 1IWG is the inner-membrane transporter protein in this system and has subunits that are present in both the cytoplasm and periplasm of the E. coli cell, which allows it to work in tandem with the TolC protein for drug export. It is believed that AcrB captures substrates mainly from the periplasm of the cell, but these substrates can still enter the inner cavity of this funnel-like protein from the cytoplasm.

Structural highlights

This protein has a molecular mass of 114 kDa and is a one chain structure that consists of 1049 amino acids, and organizes itself as a homotrimer in shape similar to that of a jellyfish. Each protomer in this protein is composed of a 50 A thick transmembrane region, as well as a protruding headpiece that is 70 A in size. It is believed by some that this headpiece section opens up at the top like a funnel, which the TolC protein can directly dock itself onto. Direct disulfide cross-linking experiments have also shown the interactions between the AcrB and TolC trimers, suggesting that the headpiece-TolC belief might be true.

AcrB is shaped like a funnel with its ends found in both the cytoplasm and periplasm of the bacterial cell. The C terminus of AcrB is located in the cell’s cytoplasm, while the N terminus links with AcrA in the periplasm. The N- and C- terminal halves of AcrB are connected to each other with an alpha-helix that runs parallel to the cytoplasmic membrane of the bacteria. Subunits within the protein have three possible conformational states, which include the access (L), binding (T), and extrusion (O) states. However, binding of substrates and inhibitors will affect the conformational states of the protein. For example, binding of the MBX3132 inhibitor creates a TTT conformation state for the protein as a whole, which makes the inhibitor bind tightly to the protein and negatively affects substrate binding/protein function.

It has first been found that a Asp-Lys-Asp triad was found to be essential in AcrB. Later, three individual subunits in the transmembrane region have been identified to play key roles in AcrB function. The has been found to be essential in the TM4 subunit in E. coli, and this residue works in conjunction with the and subunits to allow the protein to function ^[1]