Proposed model for MAC formation on surfaces, opsonized with C3b or C4b (such as pathologic red blood cells): C5, coming from the circulation (cyan), binds to one of the many C3b (green) or C4b (violet) molecules on the cell surface (rose). The interaction induces conformational change by moving the thioester domain (blue circle in C5) partially down, and exposure of the C5a domain (blue ellipse), to facilitate its cleavage by the C5 convertases. After such proteolytic activation, C5a is released, and the thioester domain in C5b goes down to its maximum extent, exposing the C6 binding site and allowing the formation of the C5b-9 MAC. This process will be blocked by stoichiometric C3 or C5 inhibitors, explaining their therapeutic effect. In the context of very high densities of C3b or C4b, the interaction with C5 is stronger, allowing full transition of the thioester domain down, assuming a C5b-like structure, without cleavage and release of the C5a domain. This newly formed C5_conf will have the C6 binding site exposed and the capacity to form a C5_conf-C9 MAC. This new process is expected to occur rarely, only at very high density of C3b or C4b and in the absence of active convertases. The formation of this C5_conf-9 membrane attach complex, though, will not be prevented by stoichiometric C3 or C5 inhibitors and may contribute to the pharmacodynamic breakthrough effect. Illustration by Margot Revel, Centre de Recherche des Cordeliers, using BioRender.com.