Alpha1-Antitrypsin: Structure and Dynamics in Health, Disease and Drug Development

Alistair Jagger*, James A. Irving, S. Tamir Rashid, David A. Lomas, Bibek Gooptu

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

3 Citations (Scopus)

Abstract

As with all proteins, the structural behavior of α1-antitrypsin determines its function. However, the functional mechanism by which α1-antitrypsin inhibits its target proteases is unusually dynamic, relating to its folding and the potential for it to adopt more thermodynamically stable forms than its native conformation. Alpha1-antitrypsin deficiency arises most commonly as a result of point mutations that affect the structure and dynamic behavior of α1-antitrypsin in solution during and after folding. Understanding the dynamic structural behavior of α1-antitrypsin, therefore, explains both how it functions in health and how it drives disease. Consequently, it identifies novel therapeutic strategies to treat the underlying pathogenic mechanisms in α1-antitrypsin deficiency.

Original languageEnglish
Title of host publicationAlpha-1-antitrypsin Deficiency: Biology, Diagnosis, Clinical Significance, and Emerging Therapies
PublisherElsevier Inc.
Pages49-80
Number of pages32
ISBN (Electronic)9780128039472
ISBN (Print)9780128039427
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • Alpha1-antitrypsin
  • Antiprotease mechanism
  • Conformational change
  • Folding
  • Gain-of-function
  • Loss-of-function
  • Misfolding
  • Molecular mechanism of disease
  • Polymerization
  • Serpinopathies
  • Structure:function relationship
  • Therapeutic targeting

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