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==High resolution structure of Alpha-1-acid glycoprotein bound to potent anti-tumour compound UCN-01== | ==High resolution structure of Alpha-1-acid glycoprotein bound to potent anti-tumour compound UCN-01== | ||
<StructureSection load='7oub' size='340' side='right'caption='[[7oub]]' scene=''> | <StructureSection load='7oub' size='340' side='right'caption='[[7oub]], [[Resolution|resolution]] 1.82Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OUB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OUB FirstGlance]. <br> | <table><tr><td colspan='2'>[[7oub]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OUB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OUB FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7oub FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7oub OCA], [https://pdbe.org/7oub PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7oub RCSB], [https://www.ebi.ac.uk/pdbsum/7oub PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7oub ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UCN:7-HYDROXYSTAUROSPORINE'>UCN</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7oub FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7oub OCA], [https://pdbe.org/7oub PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7oub RCSB], [https://www.ebi.ac.uk/pdbsum/7oub PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7oub ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/A1AG2_HUMAN A1AG2_HUMAN]] Functions as transport protein in the blood stream. Binds various hydrophobic ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability. Appears to function in modulating the activity of the immune system during the acute-phase reaction.<ref>PMID:21349832</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The 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<ref>PMID:34758357</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7oub" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Crump | [[Category: Crump, M P]] | ||
[[Category: Landin | [[Category: Landin, E J.B]] | ||
[[Category: Williams C]] | [[Category: Williams, C]] | ||
[[Category: Agp2]] | |||
[[Category: Alpha-1-acid glycoprotein]] | |||
[[Category: Complex]] | |||
[[Category: Lipocalin]] | |||
[[Category: Orm2]] | |||
[[Category: Protein transport]] | |||
[[Category: Ucn-01]] | |||
Revision as of 15:38, 22 December 2021
High resolution structure of Alpha-1-acid glycoprotein bound to potent anti-tumour compound UCN-01
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