The bacterial HPr kinase/phosphorylase: a new type of Ser/Thr kinase as antimicrobial target.
Protein phosphorylation plays a major role in bacterial cellular regulation as in eukaryotes. The HPr Kinase/Phosphorylase (HprK/P) was the first bacterial serine protein kinase to have had its structure determined, establishing that it is unrelated to the eukaryotic kinases. HprK/P belongs to another large structural family, the P-loop containing proteins. Among them, P-loop containing kinases have been assumed to only phosphorylate small molecules, but the example of HprK/P suggests that some may have proteins as substrates, defining novel cellular signal transduction pathways. Another major result of the studies presented here is that HprK/P also catalyses the phosphorolysis of the phosphoserine, yielding serine and pyrophosphate. The two different catalytic activities are carried out at the same active site. The determination of the structure of the complex with the protein substrates HPr and PserHPr allowed us to propose a catalytic mechanism. Since regulation of HPr phosphorylation has been shown to be involved in the virulence process of pathogenic bacteria, a search for specific inhibitors of HprK/P is of clinical interest and the first hit has already been found.
Nessler
Sylvie
S
Laboratoire d'Enzymologie et Biochimie Structurales, UPR 9063, CNRS, 91198-Gif-sur-Yvette, France. nessler@lebs.cnrs-gif.fr
D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000737:chemistry / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D010710:Phosphates; C110847:HPr kinase; D017346:Protein Serine-Threonine Kinases