Journal
ACS OMEGA
Volume 6, Issue 35, Pages 22876-22887Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.1c03400
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Funding
- SERB [EMR/2016/000681]
- CSIR, New Delhi
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This study provides biophysical validation of the hypothesized two-site binding interactions of C5a with C5aR1, improving understanding of the physiological and pathological roles of the complement system. The findings may advance the development of new-generation antibodies and neutraligands targeting C5a for modulating its interaction with C5aR1.
The C5a receptor's (C5aR1) physiological function in various tissues depends on its high-affinity binding to the cationic proinflammatory glycoprotein C5a, produced during the activation of the complement system. However, an overstimulated complement can quickly alter the C5a-C5aR1 function from physiological to pathological, as has been noted in the case of several chronic inflammation-induced diseases like asthma, lung injury, multiorgan failure, sepsis, and now COVID-19. In the absence of the structural data, the current study provides the confirmatory biophysical validation of the hypothesized two-site binding interactions of C5a, involving (i) the N-terminus (NT) peptide (Site1) and (ii) the extracellular loop 2 (ECL2) peptide of the extracellular surface (ECS) of the C5aR1 (Site2), as illustrated earlier in the reported model structural complex of C5a-C5aR1. The biophysical and computational data elaborated in the study provides an improved understanding of the C5a-C5aR1 interaction at an atomistic resolution, highlighting the energetic importance of the aspartic acids on the NT-peptide of C5aR1 toward binding of C5a. The current study can potentially advance the search and optimization of new-generation alternative antibodies as well as neutraligands targeting the C5a to modulate its interaction with C5aR1.
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