Related Experiment Videos
The intact and cleaved human antithrombin III complex as a model for serpin-proteinase interactions
H A Schreuder1, B de Boer, R Dijkema
1BIOSON Research Institute, University of Groningen, Nijenborgh, The Netherlands.
Nature Structural Biology
|January 1, 1994
Summary
Human antithrombin, a key proteinase inhibitor, adopts a novel intact reactive site loop conformation. This structure is optimized for binding and inhibiting target proteinases like thrombin.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Medicine
Background:
- Antithrombin is a crucial serine proteinase inhibitor (serpin) regulating blood coagulation.
- Serpins feature a reactive site loop (RSL) that interacts with and is cleaved by target proteinases.
- The RSL conformation dictates proteinase binding: latent serpins have inserted RSLs, while ovalbumin has an exposed alpha-helical RSL, neither facilitating binding.
Purpose of the Study:
- To elucidate the structural conformation of the intact and cleaved human antithrombin complex.
- To understand how antithrombin's RSL structure facilitates interaction with target proteinases.
Main Methods:
- X-ray crystallography was used to determine the structure of the intact and cleaved human antithrombin complex.
- Comparative structural analysis of antithrombin in different functional states and with other serpins.
Main Results:
- The intact antithrombin complex reveals a novel conformation of the reactive site loop.
- This newly identified RSL conformation appears ideally suited for binding to proteinases, including thrombin and blood coagulation factor Xa.
- The cleaved antithrombin structure provides insights into the mechanism of inhibition.
Conclusions:
- The novel RSL conformation in intact antithrombin is critical for its inhibitory function.
- Understanding this structure enhances our knowledge of serpin mechanism and anticoagulation.
- This structural insight may inform the development of new antithrombotic agents.