Figure 1.

The structure and mechanism of inhibitory serpins. (a) The structure of native SERPINA1 (Protein Data Bank (PDB) code 1QLP) [32]. The A sheet is in red, the B sheet in green and the C sheet in yellow; helices (hA-hI) are in blue. The reactive center loop (RCL) is at the top of the molecule, in magenta. The position of the breach and the shutter are labeled and the path of RCL insertion indicated (magenta dashed line). Both of these regions contain several highly conserved residues, many of which are mutated in various serpinopathies. (b) The Michaelis or docking complex between SERPINA1 and inactive trypsin (PDB code 1OPH) [36], with the protease (multicolors) docked onto the RCL (magenta). Upon docking with an active protease (b), two possible pathways are apparent. (c) The final serpin enzyme complex (PDB code 1EZX [12]). The serpin has undergone the S to R transition, and the protease hangs distorted at the base of the molecule. (d) The structure of cleaved SERPINA1 is shown (PDB code 7API) [93]) with the RCL (magenta) forming the fourth strand of β-sheet A. The result of serpin substrate-like behavior can be seen where the protease has escaped the conformational trap, leaving active protease and inactive, cleaved serpin. Certain serpin mutations, particularly non-conservative substitutions within the hinge region of the RCL, result in substrate-like, rather than inhibitory, behavior [94].

Law et al. Genome Biology 2006 7:216   doi:10.1186/gb-2006-7-5-216
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