7OUB
High resolution structure of Alpha-1-acid glycoprotein bound to potent anti-tumour compound UCN-01
Summary for 7OUB
| Entry DOI | 10.2210/pdb7oub/pdb |
| Descriptor | Alpha-1-acid glycoprotein 2, 7-HYDROXYSTAUROSPORINE (3 entities in total) |
| Functional Keywords | agp2, orm2, lipocalin, complex, alpha-1-acid glycoprotein, ucn-01, protein transport |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 23026.76 |
| Authors | Landin, E.J.B.,Williams, C.,Crump, M.P. (deposition date: 2021-06-11, release date: 2021-12-01, Last modification date: 2024-11-06) |
| Primary citation | Landin, E.J.B.,Williams, C.,Ryan, S.A.,Bochel, A.,Akter, N.,Redfield, C.,Sessions, R.B.,Dedi, N.,Taylor, R.J.,Crump, M.P. The structural basis for high affinity binding of alpha 1-acid glycoprotein to the potent antitumor compound UCN-01. J.Biol.Chem., 297:101392-101392, 2021 Cited by PubMed 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. PubMed: 34758357DOI: 10.1016/j.jbc.2021.101392 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.82 Å) |
Structure validation
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