ACTIVE-SITE AND EXOSITE BINDING OF ALPHA-THROMBIN

Alpha-thrombin possesses at least three independent binding sites for substrate, inhibitor and effector molecules. The S1 subsite of the active site is specific for an arginine side group while S2 is a more extended apolar site. The fibrinogen recognition exosite, which usually operates in concert with catalysis, appears to circumnavigate about a third of the surface, although evidence suggests that recognition of a tetra- or pentapeptide sequence is sufficient. Another highly electropositive region of thrombin, which binds the second kringle of prothrombin through salt bridges, is also most likely the heparin binding site. All three sites display distinct binding modes with different molecules. In the active site, these can arise from different optical enantiomorphs combined with reversal of main chain direction, while in the fibrinogen anion binding exosite, certain peptide side chains (hydrophobic) are tolerated of imprecision or are not relevant for binding or undergo a conformational change in substrate binding. Such apparently indiscriminant behaviour easily accounts for the diversity of thrombin functions at the molecular level.