期刊
SEMINARS IN IMMUNOLOGY
卷 59, 期 -, 页码 -出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.smim.2022.101627
关键词
Complement; Alternative pathway; C3; Convertase; Structural biology; Inhibitor
类别
资金
- U.S. National Institutes of Health [R35GM140852]
- Netherlands Organisation for Scientific Research (NWO)
- European Research Council (ERC) under the European Union [787241]
- European Research Council (ERC) [787241] Funding Source: European Research Council (ERC)
This review classifies, summarizes, and interprets the crystal structures of human C3 and highlights the features of C3 structure revealed by solution-based methods. It also provides insights into the future development of next-generation C3 inhibitors leveraging the growing body of structural information, as C3-targeted therapeutics begin to be used in clinical settings.
As the most abundant component of the complement system, C3 and its proteolytic derivatives serve essential roles in the function of all three complement pathways. Central to this is a network of protein-protein interactions made possible by the sequential proteolysis and far-reaching structural changes that accompany C3 activation. Beginning with the crystal structures of C3, C3b, and C3c nearly twenty years ago, the physical transformations underlying C3 function that had long been suspected were finally revealed. In the years that followed, a compendium of crystallographic information on C3 derivatives bound to various enzymes, regulators, receptors, and inhibitors generated new levels of insight into the structure and function of the C3 molecule. This Review provides a concise classification, summary, and interpretation of the more than 50 unique crystal structure determinations for human C3. It also highlights other salient features of C3 structure that were made possible through solution-based methods, including Hydrogen/Deuterium Exchange and Small Angle X-ray Scattering. At this pivotal time when the first C3-targeted therapeutics begin to see use in the clinic, some perspectives are also offered on how this continually growing body of structural information might be leveraged for future development of next-generation C3 inhibitors.
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