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Quantitative proteomics approach for identifying protein-drug interactions in complex mixtures using protein stability measurements.

Publication ,  Journal Article
West, GM; Tucker, CL; Xu, T; Park, SK; Han, X; Yates, JR; Fitzgerald, MC
Published in: Proceedings of the National Academy of Sciences of the United States of America
May 2010

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) approximately 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.

Duke Scholars

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

May 2010

Volume

107

Issue

20

Start / End Page

9078 / 9082

Related Subject Headings

  • Yeasts
  • UDPglucose 4-Epimerase
  • Thermodynamics
  • Proteomics
  • Proteins
  • Protein Folding
  • Pharmaceutical Preparations
  • Mass Spectrometry
  • Cyclosporine
  • Complex Mixtures
 

Citation

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MLA
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West, G. M., Tucker, C. L., Xu, T., Park, S. K., Han, X., Yates, J. R., & Fitzgerald, M. C. (2010). Quantitative proteomics approach for identifying protein-drug interactions in complex mixtures using protein stability measurements. Proceedings of the National Academy of Sciences of the United States of America, 107(20), 9078–9082. https://doi.org/10.1073/pnas.1000148107
West, Graham M., Chandra L. Tucker, Tao Xu, Sung Kyu Park, Xuemei Han, John R. Yates, and Michael C. Fitzgerald. “Quantitative proteomics approach for identifying protein-drug interactions in complex mixtures using protein stability measurements.Proceedings of the National Academy of Sciences of the United States of America 107, no. 20 (May 2010): 9078–82. https://doi.org/10.1073/pnas.1000148107.
West GM, Tucker CL, Xu T, Park SK, Han X, Yates JR, et al. Quantitative proteomics approach for identifying protein-drug interactions in complex mixtures using protein stability measurements. Proceedings of the National Academy of Sciences of the United States of America. 2010 May;107(20):9078–82.
West, Graham M., et al. “Quantitative proteomics approach for identifying protein-drug interactions in complex mixtures using protein stability measurements.Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 20, May 2010, pp. 9078–82. Epmc, doi:10.1073/pnas.1000148107.
West GM, Tucker CL, Xu T, Park SK, Han X, Yates JR, Fitzgerald MC. Quantitative proteomics approach for identifying protein-drug interactions in complex mixtures using protein stability measurements. Proceedings of the National Academy of Sciences of the United States of America. 2010 May;107(20):9078–9082.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

May 2010

Volume

107

Issue

20

Start / End Page

9078 / 9082

Related Subject Headings

  • Yeasts
  • UDPglucose 4-Epimerase
  • Thermodynamics
  • Proteomics
  • Proteins
  • Protein Folding
  • Pharmaceutical Preparations
  • Mass Spectrometry
  • Cyclosporine
  • Complex Mixtures