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)

Abstract

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
Volume297
Issue number6
Early online date7 Nov 2021
DOIs
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:
© 2021 THE AUTHORS.

Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute

Keywords

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

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