{"doi":"10.1101/2022.07.04.498667","title":"Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation","abstract":"Abstract The MAP kinase p38α is a central component of signalling in inflammation and the immune response and is, therefore, an important drug target. Little is known about the molecular mechanism of its activation by double-phosphorylation from MAP2Ks, due to the challenge of trapping a transient and dynamic hetero-kinase complex. Here, we applied a multidisciplinary approach to generate the first structure of p38α in complex with its MAP2K MKK6 and understand the activation mechanism. Integrating cryo-EM with MD simulations, HDX-MS and in cellulo experiments, we demonstrate a dynamic, multi-step, phosphorylation mechanism, reveal new catalytically relevant interactions, and show that MAP2K disordered N-termini determine pathway specificity. Our work captures, for the first time, a fundamental step of cell signalling: a kinase phosphorylating its downstream target kinase. One-Sentence Summary Integrative Cryo-EM and MD analysis of an active hetero-kinase complex reveals details of cellular signal transmission","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":303760,"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":0.9501,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":644219,"name":"Ioannis Galdadas","orcid":"0000-0003-2136-9723","position":1,"is_corresponding":false},{"id":996175,"name":"Dorothea Gobbo","orcid":"0000-0001-9102-710X","position":2,"is_corresponding":false},{"id":996176,"name":"Jill von Velsen","orcid":"0000-0002-1254-7842","position":3,"is_corresponding":false},{"id":996177,"name":"Martin Pelosse","orcid":"0000-0003-0840-7342","position":4,"is_corresponding":false},{"id":996178,"name":"Mark D. Tully","orcid":"0000-0001-5450-9900","position":5,"is_corresponding":false},{"id":653789,"name":"Oscar Vadas","orcid":"0000-0003-3511-6479","position":6,"is_corresponding":false},{"id":244435,"name":"Francesco Luigi Gervasio","orcid":"0000-0003-4831-5039","position":7,"is_corresponding":false},{"id":993575,"name":"Erika Pellegrini","orcid":"0000-0001-8799-3372","position":8,"is_corresponding":false},{"id":996179,"name":"Matthew W. Bowler","orcid":"0000-0003-0465-3351","position":9,"is_corresponding":false},{"id":996174,"name":"Pauline Juyoux","orcid":"0000-0003-3153-1376","position":0,"is_corresponding":true}],"reference_count":109,"raw_metadata":null,"created_at":"2026-07-19T00:32:28.468841Z","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":[]}