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Implications for function and therapy of a 2.9 A structure of binary-complexed antithrombin

R Skinner¹, W S Chang, L Jin

¹Department of Haematology, University of Cambridge, Hills Road, Cambridge, CB2 2QH, UK.

Journal of Molecular Biology

|October 8, 1998

Summary

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Human antithrombin

Area of Science:

Biochemistry
Structural Biology
Drug Design

Background:

Antithrombin is a key regulator of blood coagulation.
Serpins, including antithrombin, can polymerize in diseases like cirrhosis and thrombosis.
Reactive loop peptides are known to interfere with serpin polymerization.

Purpose of the Study:

To determine the crystal structure of a binary complex of human antithrombin with its reactive loop peptide.
To understand the mechanism of peptide binding and its effect on antithrombin conformation.
To provide a basis for designing drugs to prevent serpin polymerization.

Main Methods:

X-ray crystallography at 2.9 A resolution.
Biochemical assays to measure reaction rates with Factor Xa.

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Main Results:

The reactive loop peptide binds to the A beta-sheet, displacing the hinge region.
This binding alters antithrombin's conformation but is insufficient for full heparin activation.
The structure precisely localizes the blocking peptide within the serpin.

Conclusions:

Full loop expulsion alone does not fully activate antithrombin; overall conformation is crucial.
The determined structure provides a blueprint for developing antithrombin-based drugs.
This could lead to novel treatments for thrombosis and cirrhosis by preventing serpin polymerization.