3NE4

1.8 Angstrom structure of intact native wild-type alpha-1-antitrypsin

3NE4 の概要

• エントリーDOI: 10.2210/pdb3ne4/pdb
• 分子名称: Alpha-1-antitrypsin (2 entities in total)
• 機能のキーワード: alpha1-antitrypsin, serpin, lung disease, liver disease, polymerisation, hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted. Short peptide from AAT: Secreted, extracellular space, extracellular matrix: P01009
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47619.22

構造登録者

Patschull, A.O.M.,Gooptu, B.,Segu, L. (登録日: 2010-06-08, 公開日: 2011-12-14, 最終更新日: 2023-09-06)

主引用文献

Patschull, A.O.,Segu, L.,Nyon, M.P.,Lomas, D.A.,Nobeli, I.,Barrett, T.E.,Gooptu, B.
Therapeutic target-site variability in [alpha]1-antitrypsin characterized at high resolution
Acta Crystallogr.,Sect.F, 67:1492-1497, 2011

PubMed Abstract: The intrinsic propensity of α(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 α(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 α(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.

PubMed: 22139150
DOI: 10.1107/S1744309111040267

実験手法

X-RAY DIFFRACTION (1.81 Å)