{"doi":"10.1002/pro.70133","title":"The <scp>LptC transmembrane</scp> helix undergoes a rigid body movement upon <scp>LptB<sub>2</sub>FG</scp> cavity collapse","abstract":"Abstract Lipopolysaccharide (LPS) is an essential component of the cellular envelope of Gram‐negative bacteria and contributes to antibiotic resistance and pathogenesis. Proper localization of LPS at the outer membrane is facilitated via seven distinct LPS transport (Lpt) proteins that bridge the inner and outer membranes. Mature LPS diffuses into the membrane cavity of the inner membrane ABC transporter LptB 2 FGC through a lateral gate formed by the LptF and LptG transmembrane (TM) helices. The TM helix of LptC intercalates within the LPS entry point and has been shown to regulate the ATPase activity of LptB 2 FG and contribute to thermal stability. Determination of the LptB 2 FGC open state structure revealed the location of the LptC TM helix within the membrane complex. However, in the closed state structure, the LptC TM helix is unresolved, suggesting the helix may be displaced from the lateral gate prior to or upon closure of the cavity. To determine the conformational states of the LptC TM helix in the open and closed LptB 2 FGC conformations, we utilized site‐directed spin labeling in combination with both continuous wave electron paramagnetic resonance (EPR) and double electron electron resonance (DEER) spectroscopies to investigate the LptC TM helix and linker region. These data indicate that the LptC TM helix undergoes a rigid body movement away from the central LptB 2 FG cavity upon cavity closure. The findings presented here will support structure‐based drug design optimization of recently discovered antibiotics that bind LptB 2 FG and occlude the LptC TM helix from the lateral gate.","journal":"Protein Science","year":2025,"id":530060,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":498925,"name":"Candice S. Klug","orcid":"0000-0003-4547-320X","position":1,"is_corresponding":false},{"id":1087331,"name":"Nicholas P. Cina","orcid":null,"position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:51:01.235017Z","pmid":"40260908","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}