Lipopolysaccharide (LPS) in Gram-negative bacteria is essential for outer membrane formation and antibiotic resistance. The LPS transport proteins A-G (LptA-G) move LPS from the inner to outer membrane. The ATP-binding cassette (ABC) transporter LptB2FG, tightly associated with LptC, extracts LPS out of the inner membrane. The mechanism of the entire LptB2FGC complex and the role of LptC are poorly understood. Here, we used single-particle cryo-EM to characterize the structures of LptB2FG and LptB2FGC in the nucleotide-free and vanadate-trapped states. These cryo-EM structures resolve the bound LPS, reveal the transporter-LPS interactions with side-chain details, and uncover the basis of coupling LPS capture and extrusion to conformational rearrangements of LptB2FGC. LptC inserts its transmembrane helix between the two transmembrane domains of LptB2FG, representing an unprecedented regulatory mechanism for ABC transporters. Our results suggest a role of LptC in coordinating LptB2FG action and the periplasmic Lpt protein interactions to achieve efficient LPS transport.
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