{"doi":"10.17615/db9p-0f56","title":"Ligand recognition and allosteric modulation of the human MRGPRX1 receptor","abstract":"The human MAS-related G protein–coupled receptor X1 (MRGPRX1) is preferentially expressed in the small-diameter primary sensory neurons and involved in the mediation of nociception and pruritus. Central activation of MRGPRX1 by the endogenous opioid peptide fragment BAM8-22 and its positive allosteric modulator ML382 has been shown to effectively inhibit persistent pain, making MRGPRX1 a promising target for non-opioid pain treatment. However, the activation mechanism of MRGPRX1 is still largely unknown. Here we report three high-resolution cryogenic electron microscopy structures of MRGPRX1–Gαq in complex with BAM8-22 alone, with BAM8-22 and ML382 simultaneously as well as with a synthetic agonist compound-16. These structures reveal the agonist binding mode for MRGPRX1 and illuminate the structural requirements for positive allosteric modulation. Collectively, our findings provide a molecular understanding of the activation and allosteric modulation of the MRGPRX1 receptor, which could facilitate the structure-based design of non-opioid pain-relieving drugs.","journal":"UNC Libraries","year":2024,"id":483481,"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":1,"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":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1268325,"name":"John F. Fay","orcid":null,"position":1,"is_corresponding":false},{"id":549005,"name":"Yushi Liu","orcid":null,"position":2,"is_corresponding":false},{"id":512693,"name":"B.E Krumm","orcid":null,"position":3,"is_corresponding":false},{"id":225473,"name":"Bryan L. Roth","orcid":"0000-0002-0561-6520","position":4,"is_corresponding":false},{"id":1324613,"name":"Can Cao","orcid":"0000-0001-7011-9435","position":5,"is_corresponding":false},{"id":984322,"name":"Moira Rachman","orcid":"0000-0003-3671-8885","position":6,"is_corresponding":false},{"id":779439,"name":"Ryan H. Gumpper","orcid":"0000-0003-1309-3069","position":7,"is_corresponding":false},{"id":1311872,"name":"X.-P Huang","orcid":"0009-0000-5004-1466","position":8,"is_corresponding":false},{"id":106698,"name":"Brian K. Shoichet","orcid":"0000-0002-6098-7367","position":9,"is_corresponding":false},{"id":1324614,"name":"Shih SL","orcid":"0000-0002-6874-0529","position":10,"is_corresponding":false},{"id":1325055,"name":"Shen-Rong Zhang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:07:33.718973Z","pmid":null,"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":[]}