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

DOI: 10.1016/j.jbc.2021.101392 DOI Help

Authors: Erik J. B. Landin (University of Bristol) , Christopher Williams (University of Bristol; BrisSynBio) , Sara A. Ryan (University of Bristol) , Alice Bochel (University of Bristol) , Akter Nahida (University of Bristol) , Christina Redfield (University of Oxford) , Richard B. Sessions (University of Bristol) , Neesha Dedi (UCB Pharma) , Richard Taylor (UCB Pharma) , Matthew P. Crump (University of Bristol)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 12

State: Published (Approved)
Published: November 2021
Diamond Proposal Number(s): 23269

Open Access Open Access

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.

Journal Keywords: AGP2; UCN-01; Staurosporine; X-ray crystallography; Glycoprotein; kinase inhibitors; pharmokinetics

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 01/12/2021 08:55

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)