Hypothetical model of C5 activation and inhibition. (A) Adaptation of a model of C5 activation proposed by Jore et al.13 The scissile bond in C5 (located near the anaphylatoxin domain, C5a, which is depicted as a red triangle) is not readily accessible in free C5 for proteolytic activation by the convertase C3bBb. When C5 binds to C3b molecules, it undergoes a conformational change (a “priming event”) that renders the scissile bond accessible for proteolytic activation by a nearby convertase. (B) C5 inhibitors stabilize the unproductive C5 conformation, thus hindering the conformational priming event and, thus, the proteolytic activation of C5. However, surfaces bearing densely packed C3b molecules can compete (to some extent) with C5 inhibitors for C5 priming (ie, binding and conformational reorientation), resulting in a residual C5 activation level. Simultaneous inhibition with 2 orthogonal C5 inhibitors more effectively stabilizes the unproductive C5 conformation and prevents activation by the convertase even in presence of high C3b densities. Ecu, eculizumab; MAC, membrane attack complex.
