{"doi":"10.1021/jacs.5c07761","title":"Structural Insights into Recognition and Translocation of Oxidized Phospholipid by CD36 Using Mass Spectrometry, Molecular Docking, Dynamics, and Metadynamics Simulations","abstract":"CD36 is a multifunctional receptor widely expressed in immune and nonimmune cells, known for its role in lipid transport and inflammatory signaling. Oxidized phospholipids (oxPLs), a class of prominent lipid oxidation products generated under oxidative stress, bind CD36 with high affinity, contributing to the development of atherogenesis and thrombosis and potentially influencing other CD36-dependent biological events. The molecular basis for the oxPL-CD36 interaction is poorly understood. Here, we used cutting-edge enrichment-mass spectrometry to identify lysine residues of CD36 that directly interact with oxPLs. These residues are located along a putative ligand translocation path─spanning from the apex of the extracellular domain to the entrance, interior, and around the exit of the lipid transport tunnel. Molecular docking revealed two sets of oxPL binding poses: one within a tunnel and the other on a surface loop cluster spanning the top to midsection, including the tallest loop containing oxPL-modified K398/K403. These findings support the selective oxPL binding observed in the LC-MS/MS analysis. Molecular dynamics (MD) simulation demonstrated that the sn-1 chain and headgroup of oxPLs engage distinct CD36 residues through hydrophobic, hydrogen-bonding, and ionic interactions, optimally positioning the reactive sn-2 group for lysine modification. MD and metadynamics simulations further demonstrated oxPL translocation through the tunnel, beginning with sn-1 chain insertion, followed by reorientation at the tunnel midsection, where the sn-2 chain and sn-3 headgroup lead the molecule toward the exit. Together, these studies indicate that CD36 may serve as a transporter of individual oxPL molecules into the cell and outline a translocation pathway, key residues and binding forces involved.","journal":"Journal of the American Chemical Society","year":2025,"id":584892,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"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":825785,"name":"Khuraijam Dhanachandra Singh","orcid":"0000-0003-0506-6896","position":1,"is_corresponding":false},{"id":262175,"name":"Sadashiva S. Karnik","orcid":"0000-0003-0746-2753","position":2,"is_corresponding":false},{"id":278593,"name":"Tatiana V. Byzova","orcid":"0000-0002-2615-875X","position":3,"is_corresponding":false},{"id":278591,"name":"Eugene A. Podrez","orcid":"0000-0002-9550-6965","position":4,"is_corresponding":false},{"id":377182,"name":"Detao Gao","orcid":"0000-0002-3002-9934","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-19T02:59:16.166424Z","pmid":"41364626","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":[]}