2KO7

Solution structure of peptidyl-prolyl cis-trans isomerase from Burkholderia pseudomallei complexed with Cycloheximide-N-ethylethanoate

Summary for 2KO7

• Entry DOI: 10.2210/pdb2ko7/pdb
• NMR Information: BMRB: 16491
• Descriptor: Peptidyl-prolyl cis-trans isomerase, ethyl (4-{(2R)-2-[(1S,3S,5S)-3,5-dimethyl-2-oxocyclohexyl]-2-hydroxyethyl}-2,6-dioxopiperidin-1-yl)acetate (2 entities in total)
• Functional Keywords: cis-trans isomerase, fkbp, cycloheximide-n-ethylethanoate, complex, isomerase, rotamase, structural genomics, ssgcid, seattle structural genomics center for infectious disease
• Biological source: Burkholderia pseudomallei (Pseudomonas pseudomallei)
• Total number of polymer chains: 1
• Total formula weight: 12607.14

Authors

Zheng, S.,Leeper, T.,Varani, G.,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2009-09-11, release date: 2009-09-29, Last modification date: 2024-05-01)

Primary citation

Norville, I.H.,O'Shea, K.,Sarkar-Tyson, M.,Zheng, S.,Titball, R.W.,Varani, G.,Harmer, N.J.
The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development.
Biochem.J., 437:413-422, 2011

PubMed 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.

PubMed: 21574961
DOI: 10.1042/BJ20110345

Experimental method

SOLUTION NMR