{"doi":"10.1101/2023.01.13.523955","title":"Adrenomedullin 2/intermedin is a slow off-rate, long-acting endogenous agonist of the adrenomedullin <sub>2</sub> G protein-coupled receptor","abstract":"Abstract The signaling peptides adrenomedullin 2/intermedin (AM2/IMD), adrenomedullin (AM), and CGRP have overlapping and distinct functions in the cardiovascular, lymphatic, and nervous systems by activating three shared receptors comprised of the class B GPCR CLR in complex with a RAMP1, −2, or −3 modulatory subunit. Here, we report that AM2/IMD, which is thought to be a non-selective agonist, is kinetically selective for CLR-RAMP3, known as the AM 2 R. AM2/IMD-AM 2 R elicited substantially longer duration cAMP signaling than the eight other peptide-receptor combinations due to AM2/IMD slow off-rate binding kinetics. The regions responsible for the slow off-rate were mapped to the AM2/IMD mid-region and the RAMP3 extracellular domain. MD simulations revealed how these bestow enhanced stability to the complex. Our results uncover AM2/IMD-AM 2 R as a cognate pair with unique temporal features, define the mechanism of kinetic selectivity, and explain how AM2/IMD and RAMP3 collaborate to shape the signaling output of a clinically important GPCR.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":398159,"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":0.9595,"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":962092,"name":"Jordan A. Karim","orcid":"0000-0002-2001-5176","position":1,"is_corresponding":false},{"id":1086370,"name":"Peyton H. Gordon","orcid":null,"position":2,"is_corresponding":false},{"id":1086010,"name":"James Lennon","orcid":"0000-0002-4201-3753","position":3,"is_corresponding":false},{"id":263937,"name":"Alex Dickson","orcid":"0000-0002-9640-1380","position":4,"is_corresponding":false},{"id":328298,"name":"Augen A. Pioszak","orcid":"0000-0003-2637-8928","position":5,"is_corresponding":false},{"id":1086009,"name":"Katie M. Babin","orcid":"0000-0002-7357-393X","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T01:19:43.776284Z","pmid":"36711519","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":[]}