The structural basis for high affinity binding of α1-acid glycoprotein to the potent antitumor compound UCN-01

Erik J B Landin, Christopher Williams, Sara A Ryan, Alice Bochel, Nahida Akter, Christina Redfield, Richard B Sessions, Neesha Dedi, Richard J Taylor*, Matthew P Crump*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

4 Citations (Scopus)
64 Downloads (Pure)


The α1-acid glycoprotein (AGP) is an abundant blood plasma protein with important immunomodulatory functions coupled to endogenous and exogenous ligand binding properties. Its affinity for many drug-like structures, however, means AGP can have a significant effect on the pharmokinetics and pharmacodynamics of numerous small molecule therapeutics. Staurosporine, and its hydroxylated forms UCN-01 and UCN-02, are kinase inhibitors that have been investigated at length as anti-tumour compounds. Despite their potency, these compounds display poor pharmokinetics due to binding to both AGP variants, AGP1 and AGP2. Recent renewed interest in UCN-01 as a cytostatic protective agent prompted us to solve the structure of the AGP2/UCN-01 complex by X-ray crystallography, revealing for the first time the precise binding mode of UCN-01. Solution NMR suggests AGP2 undergoes a significant conformational change upon ligand binding, but also that it uses a common set of sidechains with which it captures key groups of UCN-01 and other small molecule ligands. We anticipate that this structure and supporting NMR data will facilitate rational re-design of small molecules that could evade AGP and therefore improve tissue distribution.

Original languageEnglish
Article number101392
JournalJournal of Biological Chemistry
Issue number6
Early online date7 Nov 2021
Publication statusPublished - 1 Dec 2021

Bibliographical note

Funding Information:
Funding and additional information—We thank the BBSRC SWBIO DTP (BB/T008741/1) for funding (E. J. B. L. and A. B.). We thank BBSRC/EPSRC for funding C. W. and the Bristol 700 MHz NMR facility through the Bristol Centre for Synthetic Biology (BB/ L01386X/1). We also thank the Commonwealth Scholarship Commission for funding (N. A.) (BDCS-2017-50). We thank EPSRC (EP/R029849/1) and the Wellcome Institutional Strategic Support Fund, John Fell Fund and Edward Penley Abraham Cephalosporin Fund at the University of Oxford, for funding the 950 MHz NMR facility.

Publisher Copyright:

Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute


  • AGP2
  • UCN-01
  • Staurosporine
  • Kinase Inhibitors
  • Glycoprotein
  • X-ray crystallography
  • pharmokinetics


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