Structural highlights
Publication Abstract from PubMedThe alpha1-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. The structural basis for high affinity binding of alpha1-acid glycoprotein to the potent anti-tumour compound UCN-01.,Landin EJB, Williams C, Ryan SA, Bochel A, Akter N, Redfield C, Sessions RB, Dedi N, Taylor RJ, Crump MP J Biol Chem. 2021 Nov 7:101392. doi: 10.1016/j.jbc.2021.101392. PMID:34758357[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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