Serpin-type protease inhibitors

Serpins consist of a conserved core of three P-sheets and eight or nine a-helices that act collectively in the inhibitory mechanism. As with the Kazal- and Kunitz-type inhibitors, the mechanism involves a surface exposed loop that is termed the reactive center loop (RCL). The RCL presents a short stretch of polypeptide sequence bearing the Pl-Pl scissile bond. Like other serine protease inhibitor families, the PI residue dominates the thermodynamics that govern the interaction between protease and inhibitor. Exposure of the PI residue to solvent is typically brokered by 15 amino acids N-terminal to the PI residue and 5 residues on the C-terminal prime side of the scissile bond. Evidence for dramatic conformational change in the inhibitory mechanism was first provided by the crystal structure of the cleaved form of ai-antitrypsin (37). In this structure and unlike the native form, the reactive center loop was not solvent exposed but occurred as an additional P-strand within the core of the structure. 

If thrombin and factor Xa, the major activated blood coagulation factors (Fig. 11.6), escape into healthy blood vessels, blood clots will develop and occlude capillaries throughout the body. Direct inhibition of these activated enzymes in the blood flow utilizes serine protease inhibitors, of which there are two common types a Kunitz inhibitor and a serpin. The former possess a Kunitz domain, a convex antiparallel (1-sheet that exactly fits into the concave active site of a serine protease, directly blocking it (lock and key mechanism). By contrast, serpins undergo complex interactions with other proteins to cause conformational changes that bait and block the catalytic action (Fig. 11.12 shows the bait). Table 11.3 fists the major coagulation inhibitors and cofactors, their targets and mechanisms of action. 

Plasmin, fibrinolysin, a serine protease catalyzing Lys-Xaa and Arg-Xaa bond cleavage similar to that of trypsin. Plasmin is the key protease in blood clot lysis, and its major natural substrates are fibrinogen and fibrin. Human plasmin is derived from plasminogen, and is a two-chain protein consisting of the A or H chain (Mr 65 kDa) and the B or L chain (Mr 27.7 kDa). The active site is located in the B chain. The various molecular forms of plasmin are inactivated by protein inhibitors such as the Kunitz type, serpins, soybean and limabean trypsin inhibitors. The most important, fast-acting inhibitor of plasmin... 

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