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

doi:10.1016/j.jbc.2021.101392

Erik J.B Landin, Christopher Williams + Show 8 more

Open Access

https://doi.org/10.1016/j.jbc.2021.101392

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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 antitumour compounds. Despite their potency, these compounds display poor pharmokinetics due to binding to both AGP variants, AGP1 and AGP2. The 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. The 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 the supporting NMR data will facilitate rational redesign of small molecules that could evade AGP and therefore improve tissue distribution.

Highlights

The alpha-1-acid glycoprotein (AGP) is an acute phase drug-binding transport protein that is abundant in the blood plasma [1]
AGP1 and AGP2 each exhibit a range of affinities (KD 10−5–10−9) for endogenous and exogenous ligands which may be specific to one AGP variant or bind both with comparable avidity [16]
To determine their different ligand-binding specificities, high resolution crystal structures of nonglycosylated AGP1 [18] and AGP2 [14] ligand complexes have been solved revealing a lipocalin type fold-based around an archetypal eight-stranded β-barrel structure

Summary

Introduction

The alpha-1-acid glycoprotein (AGP) is an acute phase drug-binding transport protein that is abundant in the blood plasma [1]. We present a crystal structure and solution NMR studies of a UCN-01–AGP2 complex. The size and orientation of UCN-01 permits a more extensive array of favorable interactions to be formed within the AGP2-binding pocket and is accompanied by significant stabilization of the structure upon ligand binding.

Results

Conclusion