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    Therapeutic target-site variability in α1-antitrypsin characterized at high resolution

    Patschull, Anathe O.M. and Segu, Lakshmi and Nyon, Mun Peak and Lomas, D.A. and Nobeli, Irene and Barrett, Tracey E. and Gooptu, Bibek (2011) Therapeutic target-site variability in α1-antitrypsin characterized at high resolution. Acta Crystallographica Section F Structural Biology and Crystallization Communications 67 (12), pp. 1492-1497. ISSN 1744-3091.

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    The intrinsic propensity of [alpha]1-antitrypsin to undergo conformational transitions from its metastable native state to hyperstable forms provides a motive force for its antiprotease function. However, aberrant conformational change can also occur via an intermolecular linkage that results in polymerization. This has both loss-of-function and gain-of-function effects that lead to deficiency of the protein in human circulation, emphysema and hepatic cirrhosis. One of the most promising therapeutic strategies being developed to treat this disease targets small molecules to an allosteric site in the [alpha]1-antitrypsin molecule. Partial filling of this site impedes polymerization without abolishing function. Drug development can be improved by optimizing data on the structure and dynamics of this site. A new 1.8 Å resolution structure of [alpha]1-antitrypsin demonstrates structural variability within this site, with associated fluctuations in its upper and lower entrance grooves and ligand-binding characteristics around the innermost stable enclosed hydrophobic recess. These data will allow a broader selection of chemotypes and derivatives to be tested in silico and in vitro when screening and developing compounds to modulate conformational change to block the pathological mechanism while preserving function.


    Item Type: Article
    Additional Information: *Former research student, no ID (PR 7.3.12)
    Keyword(s) / Subject(s): [alpha]1-antitrypsin, drug development
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Bioinformatics, Bloomsbury Centre for (Closed), Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 16 Jan 2012 15:21
    Last Modified: 02 Aug 2023 16:57


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