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PMID: 10933492 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Topography of a 2.0 A structure of alpha1-antitrypsin reveals targets for rational drug design to prevent conformational disease.

Protein science : a publication of the Protein Society ·Vol. 9 ·No. 7 ·2000-07-00 ·Pages 1274-81

Elliott PR, Pei XY, Dafforn TR, Lomas DA

Abstract

Members of the serpin family of serine proteinase inhibitors play important roles in the inflammatory, coagulation, fibrinolytic, and complement cascades. An inherent part of their function is the ability to undergo a structural rearrangement, the stressed (S) to relaxed (R) transition, in which an extra strand is inserted into the central A beta-sheet. In order for this transition to take place, the A sheet has to be unusually flexible. Malfunctions in this flexibility can lead to aberrant protein linkage, serpin inactivation, and diseases as diverse as cirrhosis, thrombosis, angioedema, emphysema, and dementia. The development of agents that control this conformational rearrangement requires a high resolution structure of an active serpin. We present here the topology of the archetypal serpin alpha1-antitrypsin to 2 A resolution. This structure allows us to define five cavities that are potential targets for rational drug design to develop agents that will prevent conformational transitions and ameliorate the associated disease.

MeSH Terms
Crystallography, X-Ray Drug Design Models, Molecular Mutation Protein Conformation Recombinant Proteins/chemistry,genetics,metabolism alpha 1-Antitrypsin/chemistry,genetics,metabolism
Chemicals
Recombinant Proteins alpha 1-Antitrypsin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Elliott P R
Department of Medicine, University of Cambridge, The Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, United Kingdom.
Pei X Y
Dafforn T R
Lomas D A
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Article Info
Journal
Protein science : a publication of the Protein Society
Abbr.
Protein Sci
ISSN
0961-8368
DOI
10.1110/ps.9.7.1274
Published
2000-07-00
Pages
1274-81
Language
English
Region
United States
NLM ID
9211750
PMCID
PMC2144685
Subset
IM
External Links
PubMed source DOI: 10.1110/ps.9.7.1274 PMC Full Text View journal details
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