LPS export porin complex, LptBCFG-A-DE, consists of LptD (Omp; OmpA; 784 aas)-LptE (RlpB; 193 aas; O.M. lipoprotein)-LptA (KdsD; YhbN; OstA small; 185 aas periplasmic chaparone protein)-LptB (KdsC; YhbG; 241 aas cytoplasmic ABC-type ATPase)-LptC (YrbK, 199aas;1 N-terminal TMS)- LptFG, part of the ABC transporter. LptDE (1:1 stoichiometry) comprise a two-protein β-barrel-lipoprotein complex in the outer membrane that assembles and exports LPS (Chng et al., 2010).  After LPS (or a precursor) is transported across the inner membrane by MsbA (3.A.1.106.1), this seven component system translocates LPS from the outer surface of the inner membrane to the outer surface of the outer membrane using ATP hydrolysis to sequentially energize transfer from one binding site to another in several steps (Freinkman et al. 2012; Okuda et al. 2012; Sherman et al. 2014).  LPS interacts with LptC and LptA sequentially before being passed to the LptD outer membrane porin, anchored by the LptE lipoprotein on the inner surface of the outer membrane.  LptF and LptG are the transmembrane consituents of the ABC pump, and LptB is the ATPase of an ABC-like system that energizes the transport using several ATP molecules (Okuda et al. 2012; Sherman et al. 2014).  LptC interconnects the LptBFG ABC system with the periplasmic LptA protein via its large periplasmic domain (Villa et al. 2013).  LptDE form a complex in the outer membrane which inserts LPS into this membrane.  The 3-D strcture of the complex shows that the LptE lipoprotein inserts into the 26 stranded barrel of LptD as a plug.  The first two strands of LptD contain prolines and are therefore distorted, possibly creating a portal for lateral diffusion of LPS into the outer leaflet of the outer membrane (Qiao et al. 2014).  The 3-d structure of the Pseudomonas aeruginosa LptA, LptH, has been solved at 2:75 Å resolution revealing a β-jellyroll fold similar to that in LptD (Bollati et al. 2015). Direct interaction of LptB and LptC has been demonstrated (Martorana et al. 2016). A specific binding site in the LptB ATPase for the coupling helices of the transmembrane LptFG complex is responsible for coupling ATP hydrolysis by LptB with LptFG function to achieve LPS extraction (Simpson et al. 2016). After biosynthesis, bacterial lipopolysaccharides (LPS) are transiently anchored to the outer leaflet of the inner membrane (IM). The ABC transporter LptB2FG extracts LPSs from the IM and transports them to the outer membrane. Luo et al. 2017 reported the crystal structure of nucleotide-free LptB2FG from P. aeruginosa. It shows that LPS transport proteins LptF and LptG each contain a TM domain (TMD), a periplasmic beta-jellyroll-like domain and a coupling helix that interacts with LptB on the cytoplasmic side. The LptF and LptG TMDs form a large outward-facing V-shaped cavity in the IM. Mutational analyses suggested that LPS may enter the central cavity laterally, via the interface of the TMD domains of LptF and LptG, and is expelled into the beta-jellyroll-like domains upon ATP binding and hydrolysis by LptB. These studies suggest a mechanism for LPS extraction by LptB₂FG that is distinct from those of classical ABC transporters that transport substrates across the IM (Luo et al. 2017). Transport involves a stable association between the inner (LptBFG) and outer  (LptDE) membrane components, supporting a mechanism in which lipopolysaccharide molecules are pushed one after the other across a protein bridge (LptCA) that connects the inner and outer membranes (Sherman et al. 2018).  The ABC transporter, LptB₂FG, which tightly associates with LptC, extracts lipopolysaccharide out of the inner membrane.Li et al. 2019 characterized the structures of LptB2FG and LptB2FGC in nucleotide-free and vanadate-trapped states, using single-particle cryo-electron microscopy. These structures resolve the bound lipopolysaccharide, reveal transporter-lipopolysaccharide interactions with side-chain details and uncover how the capture and extrusion of lipopolysaccharide are coupled to conformational rearrangements of LptB₂FGC. LptC inserts its TMS between the two transmembrane domains of LptB₂FG, which represents a previously unknown regulatory mechanism for ABC transporters. These results suggest a role for LptC in achieving efficient lipopolysaccharide transport, by coordinating the action of LptB₂FG in the inner membrane and Lpt protein interactions in the periplasm (Li et al. 2019). cryo-EM structures of LptB₂FG alone and complexed with LptC are known, revealing conformational changes between these states. Two functional transmembrane arginine-containing loops interact with bound AMP-PNP which induces an inward rotation and shift of the transmembrane helices of LptFG and LptC to tighten the cavity, with the closure of two lateral gates, to eventually expel LPS into the bridge (Tang et al. 2019). The ABC transporter, LptB2FGC extracts LPS from the inner membrane and places it onto a periplasmic protein bridge. Lundstedt et al. 2020 showed that residue E86 of LptB is essential for coupling the function of this ATPase to that of its membrane partners, LptFG, at the step where ATP binding drives the closure of the LptB dimer and the collapse of the LPS-binding cavity in LptFG that moves LPS to the Lpt periplasmic bridge consisting of LptC, A and D (from inside to out) and then to the outer membrane insertase, LptE. Defects caused by changing residue E86 are suppressed by mutations altering either the LPS structure or TMSs in LptG. These suppressors fix defects in the coupling helix of LptF, but not of LptG. These observations support a transport mechanism in which the ATP-driven movements of LptB and those of the substrate-binding cavity in LptFG are bi-directionally coordinated through the rigid-body coupling, with LptF's coupling helix being important in coordinating cavity collapse with LptB dimerization (Lundstedt et al. 2020). The TMS of LptC participates in LPS extraction by the LptB₂ FGC transporter (Wilson and Ruiz 2022). A small molecule, IMB-0042, inhibits the interaction of LPS transporter proteins, LptA and LptC. This give rise to filament morphology, impaired OM integrity, and an accumulation of LPS in the periplasm (Dai et al. 2022). Macrocyclic peptide (MCP) antibiotics have potent antibacterial activity and represent a new class of antibiotics (Zampaloni et al. 2024), and LptB₂FGC is target. Pahil et al. 2024 showed that novel antibiotics trap a substrate-bound conformation of the LPS transporter that stalls this machine. The inhibitors accomplish this by recognizing a composite binding site made up of both the Lpt transporter and its LPS substrate. The identity of an unusual mechanism of lipid transport inhibition reveals a druggable conformation of the Lpt transporter and provides the foundation for extending this class of antibiotics to other Gram-negative pathogens (Pahil et al. 2024).  Residues within the LptC transmembrane helix are critical for E. coli LptB(2) FG ATPase (Cina et al. 2024).  Regulation of the LPS entry gate occurs through the dynamic behavior of the LptC transmembrane helix, while its β-jellyroll domain is anchored in the periplasm, and long-range ATP-dependent allosteric gating of the LptF β-jellyroll domain may ensure efficient and unidirectional transport of LPS across the periplasm (Dajka et al. 2024).  The lipopolysaccharide transport (Lpt) complex, consisting of seven proteins (A-G), exports LPS across the cellular envelope. LptB₂FG forms an ATP-binding cassette transporter that transfers LPS to LptC. Dajka et al. 2024 observed the conformational heterogeneity of LptB₂FG and LptB₂FGC in micelles and/or proteoliposomes using pulsed dipolar electron spin resonance spectroscopy. Additionally, they monitored LPS binding and release using laser-induced liquid bead ion desorption mass spectrometry. The β-jellyroll domain of LptF stably interacts with the LptG and LptC β-jellyrolls in both the apo and vanadate-trapped states. ATP binding at the cytoplasmic side is allosterically coupled to the selective opening of the periplasmic LptF β-jellyroll domain. In LptB₂FG, ATP binding closes the nucleotide binding domains, causing a collapse of the first lateral gate as observed in structures. However, the second lateral gate, which forms the putative entry site for LPS, exhibits a heterogeneous conformation. LptC binding limits the flexibility of this gate to two conformations, likely representing the helix of LptC as either released from or inserted into the transmembrane domains. These results reveal the regulation of the LPS entry gate through the dynamic behavior of the LptC transmembrane helix, while its β-jellyroll domain is anchored in the periplasm. This, combined with long-range ATP-dependent allosteric gating of the LptF β-jellyroll domain, may ensure efficient and unidirectional transport of LPS across the periplasm (Dajka et al. 2024).