{"doi":"10.1016/j.celrep.2024.114942","title":"High-affinity agonists reveal recognition motifs for the MRGPRD GPCR","abstract":"The human MRGPRD protein is a member of the Mas-related G protein-coupled receptors (MRGPRs) that is involved in the sensing of pain, itch, and other inflammatory stimuli. As with other MRGPRs, MRGPRD is a relatively understudied receptor with few known agonists. The most potent small-molecule agonist of MRGPRD reported so far is β-alanine, with an affinity in the micromole range, which largely restricts its functional study. Here, we report two MRGPRD agonists, EP-2825 and EP-3945, that are approximately 100-fold more potent than β-alanine and determine the structures of MRGPRD-Gq in complex with EP-2825 and EP-3945, respectively. The structures reveal distinct agonist binding modes of MRGPRD and large conformational plasticity of the orthosteric pocket. Collectively, the discovery of high-affinity MRGPRD agonists and their distinct binding modes will facilitate the functional study and the structure-based design of ligands targeting this understudied receptor.","journal":"Cell Reports","year":2024,"id":443744,"datarank":0.36749231029558393,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.03790862369515096,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.03790862369515096,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":8,"citers_with_citation_signal":3,"citers_with_endowment":3,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":true,"deposit_databanks":{"PDB":["9DQH","9DQJ"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":103671,"name":"Yongfeng Liu","orcid":"0000-0002-8649-7892","position":1,"is_corresponding":false},{"id":1203864,"name":"Marion Lanier","orcid":"0000-0001-5167-7263","position":2,"is_corresponding":false},{"id":1258931,"name":"Adam R. Yeager","orcid":null,"position":3,"is_corresponding":false},{"id":860486,"name":"Isha Singh","orcid":"0000-0003-3612-5393","position":4,"is_corresponding":false},{"id":779439,"name":"Ryan H. Gumpper","orcid":"0000-0003-1309-3069","position":5,"is_corresponding":false},{"id":225469,"name":"B. Krumm","orcid":"0000-0001-6039-4767","position":6,"is_corresponding":false},{"id":494653,"name":"Chelsea DeLeon","orcid":null,"position":7,"is_corresponding":false},{"id":263121,"name":"Shicheng Zhang","orcid":"0000-0002-5245-443X","position":8,"is_corresponding":false},{"id":1204747,"name":"Marcus F. Boehm","orcid":null,"position":9,"is_corresponding":false},{"id":759340,"name":"Richard Pittner","orcid":null,"position":10,"is_corresponding":false},{"id":1258932,"name":"Alain Baron","orcid":null,"position":11,"is_corresponding":false},{"id":1204742,"name":"Lisa Dvorak","orcid":null,"position":12,"is_corresponding":false},{"id":1204737,"name":"Corinne Bacon","orcid":null,"position":13,"is_corresponding":false},{"id":106698,"name":"Brian K. Shoichet","orcid":"0000-0002-6098-7367","position":14,"is_corresponding":false},{"id":1204746,"name":"Esther Martinborough","orcid":null,"position":15,"is_corresponding":false},{"id":613043,"name":"Jonathan F. Fay","orcid":"0000-0003-1822-2384","position":16,"is_corresponding":false},{"id":1032361,"name":"Can Cao","orcid":"0000-0001-6125-0837","position":17,"is_corresponding":false},{"id":225473,"name":"Bryan L. Roth","orcid":"0000-0002-0561-6520","position":18,"is_corresponding":false},{"id":255565,"name":"Chunyu Wang","orcid":"0000-0001-5165-7959","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:01:29.001453Z","pmid":"39580805","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":[]}