Three papers in this issue report the first X-ray structures of C3b, the active form of human complement C3. The complement system is a family of blood serum proteins and cell-surface receptors that recognizes pathogens and unleashes the immune response against them. The powerhouse of the C3 protein is a thioester group: when activated it binds to an acceptor on the pathogen and marks it for destruction. There are similar thioesters in host cells too, so the C3 thioester has to be kept tightly under wraps. Knowledge of the structure of the active form of C3b is a step towards designing therapies to manipulate the complement system. Inappropriate activation of the complement system has been implicated in various diseases including arthritis, asthma, lupus erythematosus, autoimmune heart disease and multiple sclerosis. Resistance to infection and clearance of cell debris in mammals depend on the activation of the complement system, which is an important component of innate and adaptive immunity1,2. Central to the complement system is the activated form of C3, called C3b, which attaches covalently to target surfaces3 to amplify complement response, label cells for phagocytosis and stimulate the adaptive immune response. C3b consists of 1,560 amino-acid residues and has 12 domains. It binds various proteins and receptors to effect its functions4. However, it is not known how C3 changes its conformation into C3b and thereby exposes its many binding sites. Here we present the crystal structure at 4-Å resolution of the activated complement protein C3b and describe the conformational rearrangements of the 12 domains that take place upon proteolytic activation. In the activated form the thioester is fully exposed for covalent attachment to target surfaces and is more than 85 Å away from the buried site in native C3 (ref. 5). Marked domain rearrangements in the α-chain present an altered molecular surface, exposing hidden and cryptic sites that are consistent with known putative binding sites of factor B and several complement regulators. The structural data indicate that the large conformational changes in the proteolytic activation and regulation of C3 take place mainly in the first conversion step, from C3 to C3b. These insights are important for the development of strategies to treat immune disorders that involve complement-mediated inflammation.

Structure of C3b reveals conformational changes that underlie complement activity