Deciphering complement mechanisms: The contributions of structural biology

Abstract

Since the resolution of the first three-dimensional structure of a complement component in 1980, considerable efforts have been put into the investigation of this system through structural biology techniques, resulting in about a hundred structures deposited in the Protein Data Bank by the beginning of 2007. By revealing its mechanisms at the atomic level, these approaches significantly improve our understanding of complement, opening the way to the rational design of specific inhibitors. This review is co-authored by some of the researchers currently involved in the structural biology of complement and its purpose is to illustrate, through representative examples, how X-ray crystallography and NMR techniques help us decipher the many sophisticated mechanisms that underlie complement functions.

Antibody equivalent molecules of the innate immune system: parallels between innate and adaptive immune proteins

“…The difference is that C1q recognizes pathogens via IgG in a two-step process whereas collectins identify their targets directly in a one-step process. 2,8,12 Different forms of MBL (e.g. MBL-A, MBL-C) and ficolins (e.g.…”

Kinetic Dissection of the Pre-existing Conformational Equilibrium in the Trypsin Fold

“…Although much is known on the structural underpinnings of these interactions and the ensuing catalytic cycle leading to cleavage of the peptide bond downstream of the residue of substrate making contact with residue 189 (5), relatively little is known on whether substrate recognition entails conformational rearrangements that precede and/or follow the binding event. Lack of information on the mechanism of substrate recognition that precedes and informs catalysis makes it difficult to interpret the allosteric effect of cofactors so widely represented in trypsin-like enzymes involved in blood coagulation (6) and the complement (7).…”

Exposure of R169 controls protein C activation and autoactivation

“…For example, complement factors B and C2 are mostly inactive until binding of complement factors C3b and C4b enables catalytic activity at the site where amplification of C3 activation leads to formation of the membrane attack complex. 3,5,6 Complement factor D assumes an inactive conformation with a distorted catalytic triad 7,8 until binding to C3b and factor B promote substrate binding and catalytic activity. 9,10 Clotting factor VIIa circulates in the blood as a poorly active protease but acquires full catalytic activity on interaction with tissue factor exposed to the bloodstream on vascular injury.…”