{"doi":"10.1016/j.jbc.2023.105353","title":"Identification of the functional PD-L1 interface region responsible for PD-1 binding and initiation of PD-1 signaling","abstract":"The PD-1/PD-L1 checkpoint pathway is important for regulating immune responses and can be targeted by immunomodulatory drugs to treat a variety of immune disorders. However, the precise protein-protein interactions required for the initiation of PD-1/PD-L1 signaling are currently unknown. Previously, we designed a series of first-generation PD-1 targeting peptides based on the native interface region of programmed death ligand 1 (PD-L1) that effectively reduced PD-1/PD-L1 binding. In this work, we further characterized the previously identified lead peptide, MN1.1, to identify key PD-1 binding residues and design an optimized peptide, MN1.4. We show MN1.4 is significantly more stable than MN1.1 in serum and retains the ability to block PD-1/PD-L1 complex formation. We further characterized the immunomodulatory effects of MN1.4 treatment by measuring markers of T cell activation in a co-culture model with ovarian cancer cells and peripheral blood mononuclear cells. We found MN1.4 treatment reduced cytokine secretion and suppressed T cell responses in a similar manner as recombinant PD-L1. Therefore, the PD-L1 interface region used to design MN1.4 appeared sufficient to initiate PD-1 signaling and likely represents the minimum necessary region of PD-L1 required for PD-1 recognition. We propose a peptide agonist for PD-1, such as MN1.4, could have several applications for treating autoimmune disorders caused by PD-1 deficiencies such as type 1 diabetes, inflammatory arthritis, or autoimmune side effects arising from monoclonal antibody-based cancer immunotherapies.","journal":"Journal of Biological Chemistry","year":2023,"id":351832,"datarank":0.3453877639491069,"base_score":2.302585092994046,"endowment":2.302585092994046,"self_citation_contribution":0.3453877639491069,"citation_network_contribution":0.0,"self_endowment_contribution":0.3453877639491069,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9608,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1096865,"name":"Fatimah Alanazi","orcid":"0000-0001-5349-3628","position":1,"is_corresponding":false},{"id":674693,"name":"Amanda K. Sharp","orcid":null,"position":2,"is_corresponding":false},{"id":1096866,"name":"Jessica Roman","orcid":"0000-0003-0454-1974","position":3,"is_corresponding":false},{"id":424770,"name":"Alessandra Luchini","orcid":"0000-0003-1599-0214","position":4,"is_corresponding":false},{"id":242177,"name":"Lance A. Liotta","orcid":"0000-0001-5155-7907","position":5,"is_corresponding":false},{"id":648224,"name":"Mikell Paige","orcid":"0000-0001-9292-1277","position":6,"is_corresponding":false},{"id":411278,"name":"Anne M. Brown","orcid":"0000-0001-6951-8228","position":7,"is_corresponding":false},{"id":563097,"name":"Amanda Haymond","orcid":"0000-0002-9553-275X","position":8,"is_corresponding":false},{"id":1096864,"name":"Rachel Carter","orcid":"0000-0002-5807-0832","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:12:45.897709Z","pmid":"37858677","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":[]}