Fig. 1.

Protein structure of inhibitory serpins. (A) The native or stressed (S) conformation. The five-stranded β-sheet A is shown in green. The RCL shown at the top in red includes the specificity-determining bait “P₁” residue (side chain is shown), which is exposed and free to interact with protease. In the inhibitory reaction, the protease approaches from the top, binds reversibly at the P₁ site, and initiates proteolysis by forming a covalent acyl “intermediate” bond at P₁ and cleaving after P₁. Cleavage releases the S conformation, allowing opening of β-sheet A and rapid topological conversion to the relaxed (R) conformation. (B) The serpin–protease complex. The serpin is in the R conformation. Note that the cleaved RCL has been inserted in the center of the serpin as an additional strand in β-sheet A and has dragged the covalently bound protease (shown in blue) by >70 Å to the opposite end of the serpin. The mechanism, called “kinetic trapping,” irreversibly inactivates the protease by gross distortion of its catalytic center. Protein coordinates in A and B are from α1-antitrypsin (SERPINA1) in the native state (1QLP) and in complex with protease (1EZX), respectively. Sheet B is shown in yellow, sheet C in pink, and the nine helices in orange.