The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development

Isobel H Norville , Katherine O'Shea , Mitali Sarkar-Tyson , Suxin Zheng , Richard W Titball , Gabriele Varani , Nicholas J Harmer (1)

1 Biosciences

Macrophage infectivity potentiators (Mips) are a subset of immunophilins associated with virulence in a range of micro-organisms. These proteins possess prolyl-peptide isomerase activity and are inhibited by drugs including rapamycin and tacrolimus. We determined the structure of the Mip homologue (BpML1) from the human pathogen and biowarfare threat Burkholderia pseudomallei by nuclear magnetic resonance 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 TGFb receptor 1 with the human immunophilin FKBP12. Furthermore, the structure of BpML1 bound to the class inhibitor cycloheximide N-ethylethanoate showed that this inhibitor mimics such a helical peptide, in contrast to 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 prolyl-peptide isomerase activity, and that some roles of Mip proteins in virulence are independent of their prolyl-peptide isomerase activity.

Mots clés: Life Sciences

Isobel H Norville, Katherine O'Shea, Mitali Sarkar-Tyson, Suxin Zheng, Richard W Titball, et al.. The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development. Biochemical Journal, 2011, 437 (3), pp.413-422. ⟨10.1042/BJ20110345⟩. ⟨hal-00608383⟩