The complement system is an important part of the immune system and critical for the elimination of pathogens. In mammals the complement system consists of an intricate set of about 35 soluble and cell-surface plasma proteins. Central to complement is component C3, a large protein of 1,641 residues. Activation of C3 into C3b leads to several molecular and cellular responses, and to stimulation of the adaptive immune system. Chapter 1 gives an overview of the complement system, the central complement component C3 and its activation products. We solved the crystal structures of human, native C3 and its final main proteolytic fragment C3c which are described in chapter 2. These structures show in detail the composition of C3. C3 consists of thirteen domains of which nine were not recognised by previous sequence analysis. The structures indicate that the proteins of the C3/alpha2-macroglobulin family may have evolved from a core of eight homologous domains. The highly reactive thioester, essential for covalent attachment to target surfaces, is protected within C3 from reaction with water by a double mechanism. The changes that take place upon activation of C3 into C3b are revealed by the crystal structure of human C3b and are described in chapter 3. The thioester is activated and fully exposed for covalent attachment over 85 Å away from its buried position in C3. Large conformational changes in the alpha-chain present a changed molecular surface exposing and forming cryptic binding sites for many ligands which are essential for the biological activity and regulation of C3b. Undue complement activation is a major cause of tissue injury and associated with many inflammatory diseases. The activation of C3 into C3b is a key step of the complement response. The thirteen residue peptide, compstatin, inhibits the activation of C3. In chapter 4 we describe the crystal structure of C3c in complex with compstatin. The structure shows that compstatin binds to domains MG4 and MG5 of the stable MG-ring. Compstatin does not induce a structural change in C3c; however, compstatin itself undergoes a large conformational change upon binding. Possibly compstatin binds to an exosite on C3 for substrate binding to the convertase and thereby sterically hinders C3 activation. This structure, together with the structures of C3, C3b and C3c, may lead to enhanced compstatin analogues and create new opportunities for drug design to target a wide variety of immune complex diseases. In the past two years long-awaited advances in structural biology of the central steps of complement activity have provided a wealth of information. In chapter 5 we discuss the recently solved crystal structure of factor B and the crystal and electron-microscopy structures of C3 and all of its activation products. We relate the structural insights of these molecules to their biological function in the complement response. In summary, the crystal structures of the central complement component C3, its activation products C3b and C3c, and C3c in complex with an inhibitor are described in this thesis. These structures indicate an intricate conformational pathway that determines the biological activity of these molecules
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