Details

Autor(en) / Beteiligte

• Cargnelutti, Maria Thereza
• Marques, Adriana Fonseca
• Esser, Daniel
• Monteiro, Robson Q.
• Kassack, Matthias U.
• Lima, Luis Mauricio T.R.

Titel

Allosteric activation of human α-thrombin through exosite 2 by suramin analogs

Ist Teil von

• Archives of biochemistry and biophysics, 2012-04, Vol.520 (1), p.36-41

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• [Display omitted] ► Suramin binds to thrombin through exosite 2. ► Suramin activates thrombin at low micromolar range. ► At higher suramin concentration thrombin is inhibited. ► A series of suramin analogs reveals the mechanism for activation and inhibition. Thrombin is a serine protease that plays fundamental roles in hemostasis. We have recently elucidated the crystal structure of thrombin in complex with suramin, evidencing the interaction through the anion binding exosite 2. Here, we show that the activity of thrombin toward natural and synthetic substrates is enhanced by suramin as well as analogs of suramin at a low micromolar range prior to an inhibitory component at higher concentrations. Suramin analogs substituted by phenyl and chlorine instead of methyl were the most efficient in promoting allosteric activation, with an enhancement of enzymatic activity of 250% and 630% respectively. We discuss the importance of exosite 2 as a regulatory site for ligands in both the procoagulant and inhibitory scenarios.