Inhibitory conformation of the reactive loop of alpha 1-antitrypsin.
The reactive site loop of the serpin family of serine proteinase inhibitors is flexible and can adopt a number of diverse conformations. A 2.9 A resolution structure of alpha 1-antitrypsin-the principal proteinase inhibitor in human plasma-shows the loop in a stable canonical conformation matching that found in all other families of serine proteinase inhibitors. This unexpected finding in the absence of loop insertion into the body of the molecule favours a two-stage mechanism of inhibition and provides a model for the heparin activation of antithrombin. The beta-pleated strand conformation of the loop also accounts for the polymerization of the serpins in disease and for their association with other beta-sheet structures, most notably the beta-amyloid of Alzheimer's disease.
Elliott
P R
PR
Department of Haematology, University of Cambridge, UK.
Lomas
D A
DA
Carrell
R W
RW
Abrahams
J P
JP
D018360:Crystallography, X-Ray; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology; D008958:Models, Molecular; D009154:Mutation; D011108:Polymers; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D000515:alpha 1-Antitrypsin / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics / Q000648:ultrastructure
D011108:Polymers; D000515:alpha 1-Antitrypsin; D006493:Heparin