Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 20, Pages 9078-9082Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1000148107
Keywords
cyclosporine; liquid chromatography-mass spectrometry; ligand binding; protein folding; thermodynamics
Categories
Funding
- National Science Foundation [CHE-08-48462]
- National Institutes of Health (NIH) [R01 HL079442, P41 RR011823]
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [0848462] Funding Source: National Science Foundation
Ask authors/readers for more resources
Knowledge about the protein targets of therapeutic agents is critical for understanding drug mode of action. Described here is a mass spectrometry-based proteomics method for identifying the protein target(s) of drug molecules that is potentially applicable to any drug compound. The method, which involves making thermodynamic measurements of protein-folding reactions in complex biological mixtures to detect protein-drug interactions, is demonstrated in an experiment to identify yeast protein targets of the immunosuppressive drug, cyclosporin A (CsA). Two of the ten protein targets identified in this proof of principle work were cyclophilin A and UDP-glucose-4-epimerase, both of which are known to interact with CsA, the former through a direct binding event (K-d similar to 70 nM) and the latter through an indirect binding event. These two previously known protein targets validate the methodology and its ability to detect both the on-and off-target effects of protein-drug interactions. The other eight protein targets discovered here, which include several proteins involved in glucose metabolism, create a new framework in which to investigate the molecular basis of CsA side effects in humans.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available