title: The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development.
abstract: Mips (macrophage infectivity potentiators) are a subset of immunophilins associated with virulence in a range of micro-organisms. These proteins possess peptidylprolyl isomerase activity and are inhibited by drugs including rapamycin and tacrolimus. We determined the structure of the Mip homologue [BpML1 (Burkholderia pseudomallei Mip-like protein 1)] from the human pathogen and biowarfare threat B. pseudomallei by NMR and X-ray crystallography. The crystal structure suggests that key catalytic residues in the BpML1 active site have unexpected conformational flexibility consistent with a role in catalysis. The structure further revealed BpML1 binding to a helical peptide, in a manner resembling the physiological interaction of human TGFβRI (transforming growth factor β receptor I) with the human immunophilin FKBP12 (FK506-binding protein 12). Furthermore, the structure of BpML1 bound to the class inhibitor cycloheximide N-ethylethanoate showed that this inhibitor mimics such a helical peptide, in contrast with the extended prolyl-peptide mimicking shown by inhibitors such as tacrolimus. We suggest that Mips, and potentially other bacterial immunophilins, participate in protein-protein interactions in addition to their peptidylprolyl isomerase activity, and that some roles of Mip proteins in virulence are independent of their peptidylprolyl isomerase activity.
authors.affiliation: School of Biosciences, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK.
authors.forename: Isobel H
authors.initials: IH
authors.lastname: Norville
authors.forename: Katherine
authors.initials: K
authors.lastname: O'Shea
authors.forename: Mitali
authors.initials: M
authors.lastname: Sarkar-Tyson
authors.forename: Suxin
authors.initials: S
authors.lastname: Zheng
authors.forename: Richard W
authors.initials: RW
authors.lastname: Titball
authors.forename: Gabriele
authors.initials: G
authors.lastname: Varani
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Harmer
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D016957:Burkholderia pseudomallei / Q000378:metabolism* / Q000472:pathogenicity; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D020104:Immunophilins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D014774:Virulence
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins