The article provides a comprehensive overview of the molecular and structural mechanisms of complement activation and regulation. Complement is a complex innate immune system that plays a crucial role in defense against pathogens and maintaining host homeostasis. The system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals, leading to a cascade of enzymatic reactions that are tightly regulated to ensure specific and controlled activation at sites requiring defense against pathogens, while avoiding damage to host tissues. The article discusses the recent advances in understanding the molecular and structural basis of activation and regulation of the complement pathways, including the classical, alternative, and lectin pathways. It covers the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack complex. The importance of structure-function relationships is highlighted using the example of atypical hemolytic uremic syndrome (aHUS). Additionally, the development and benefits of therapies using complement inhibitors are explored. Key points include: - The alternative pathway is permanently active due to spontaneous transformation of C3 to bioactive C3(H2O), which generates C3b and inactivates by FH and F1. - The classical and lectin pathways are activated by binding to apoptotic cells, leading to low-level activation and silent clearance of apoptotic cells. - Complement activation during infection involves the amplification loop, leading to inflammation, opsonization, phagocytosis, and destruction of pathogens. - The role of target recognition molecules (C1q, MBL, and ficolins) in initiating the classical and lectin pathways, and the mechanisms of activation. - Regulation of the classical and lectin pathways by C1 inhibitor and MASP inhibitors, respectively. - Platforms for surface assembly of the alternative pathway C3 convertase, such as properdin, CFHRA4, and P-selectin. - Structure and function of the C3 convertases in the alternative and classical pathways. - Negative regulation of C3 convertases by factors like Factor I, FH, MCP, DAF, and CR1. - The role of Factor H as the master regulator of the alternative pathway, competing with FB for binding to C3b and regulating the amplification loop. The article emphasizes the importance of understanding the molecular and structural mechanisms of complement activation and regulation to develop targeted therapies for complement-mediated diseases.The article provides a comprehensive overview of the molecular and structural mechanisms of complement activation and regulation. Complement is a complex innate immune system that plays a crucial role in defense against pathogens and maintaining host homeostasis. The system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals, leading to a cascade of enzymatic reactions that are tightly regulated to ensure specific and controlled activation at sites requiring defense against pathogens, while avoiding damage to host tissues. The article discusses the recent advances in understanding the molecular and structural basis of activation and regulation of the complement pathways, including the classical, alternative, and lectin pathways. It covers the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack complex. The importance of structure-function relationships is highlighted using the example of atypical hemolytic uremic syndrome (aHUS). Additionally, the development and benefits of therapies using complement inhibitors are explored. Key points include: - The alternative pathway is permanently active due to spontaneous transformation of C3 to bioactive C3(H2O), which generates C3b and inactivates by FH and F1. - The classical and lectin pathways are activated by binding to apoptotic cells, leading to low-level activation and silent clearance of apoptotic cells. - Complement activation during infection involves the amplification loop, leading to inflammation, opsonization, phagocytosis, and destruction of pathogens. - The role of target recognition molecules (C1q, MBL, and ficolins) in initiating the classical and lectin pathways, and the mechanisms of activation. - Regulation of the classical and lectin pathways by C1 inhibitor and MASP inhibitors, respectively. - Platforms for surface assembly of the alternative pathway C3 convertase, such as properdin, CFHRA4, and P-selectin. - Structure and function of the C3 convertases in the alternative and classical pathways. - Negative regulation of C3 convertases by factors like Factor I, FH, MCP, DAF, and CR1. - The role of Factor H as the master regulator of the alternative pathway, competing with FB for binding to C3b and regulating the amplification loop. The article emphasizes the importance of understanding the molecular and structural mechanisms of complement activation and regulation to develop targeted therapies for complement-mediated diseases.