{"doi":"10.1016/j.jbc.2021.100771","title":"Structural basis of KdpD histidine kinase binding to the second messenger c-di-AMP","abstract":"The KdpDE two-component system regulates potassium homeostasis and virulence in various bacterial species. The KdpD histidine kinases (HK) of this system contain a universal stress protein (USP) domain which binds to the second messenger cyclic-di-adenosine monophosphate (c-di-AMP) for regulating transcriptional output from this two-component system in Firmicutes such as Staphylococcus aureus. However, the structural basis of c-di-AMP specificity within the KdpD-USP domain is not well understood. Here, we resolved a 2.3 crystal structure of the S. aureus KdpD-USP domain (USP Sa ) complexed with c-di-AMP. Binding affinity analyses of USP Sa mutants targeting the observed USP Sa :c-di-AMP structural interface enabled the identification of the sequence residues that are required for c-di-AMP specificity. Based on the conservation of these residues in other Firmicutes, we identified the binding motif, (A/G/C)XSXSX 2 N(Y/F), which allowed us to predict c-di-AMP binding in other KdpD HKs. Furthermore, we found that the USP Sa domain contains structural features distinct from the canonical standalone USPs that bind ATP as a preferred ligand. These features include inwardfacing conformations of its 1-1 and 4-4 loops, a short 2 helix, the absence of a triphosphate-binding Walker A motif, and a unique dual phospho-ligand binding mode. It is therefore likely that USP Sa -like domains in KdpD HKs represent a novel subfamily of the USPs.","journal":"Journal of Biological Chemistry","year":2021,"id":178413,"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":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9431,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":255907,"name":"Mona Batish","orcid":"0000-0001-9039-6149","position":1,"is_corresponding":false},{"id":500675,"name":"Vijay Parashar","orcid":"0000-0002-7518-0400","position":2,"is_corresponding":false},{"id":500674,"name":"Anirudha Dutta","orcid":"0000-0003-3713-3096","position":0,"is_corresponding":true}],"reference_count":96,"raw_metadata":null,"created_at":"2026-07-18T23:47:40.592580Z","pmid":"33989637","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":[]}