title: Structural basis of mannan-binding lectin recognition by its associated serine protease MASP-1: implications for complement activation.
abstract: Complement activation contributes directly to health and disease. It neutralizes pathogens and stimulates immune processes. Defects lead to immunodeficiency and autoimmune diseases, whereas inappropriate activation causes self-damage. In the lectin and classical pathways, complement is triggered upon recognition of a pathogen by an activating complex. Here we present the first structure of such a complex in the form of the collagen-like domain of mannan-binding lectin (MBL) and the binding domain of its associated protease (MASP-1/-3). The collagen binds within a groove using a pivotal lysine side chain that interacts with Ca(2+)-coordinating residues, revealing the essential role of Ca(2+). This mode of binding is prototypic for all activating complexes of the lectin and classical pathways, and suggests a general mechanism for the global changes that drive activation. The structural insights reveal a new focus for inhibitors and we have validated this concept by targeting the binding pocket of the MASP.
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, LE1 9HN, UK.
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Gingras
authors.forename: Umakhanth Venkatraman
authors.initials: UV
authors.lastname: Girija
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Keeble
authors.forename: Roshni
authors.initials: R
authors.lastname: Panchal
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Mitchell
authors.forename: Peter C E
authors.initials: PC
authors.lastname: Moody
authors.forename: Russell
authors.initials: R
authors.lastname: Wallis
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry; D003167:Complement Activation; D056831:Coordination Complexes / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D037601:Mannose-Binding Lectin / Q000737:chemistry*; D050606:Mannose-Binding Protein-Associated Serine Proteases; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D013816:Thermodynamics
chemical_list: D056831:Coordination Complexes; D037601:Mannose-Binding Lectin; D050606:Mannose-Binding Protein-Associated Serine Proteases; C570411:Masp1 protein, rat; D002118:Calcium