Structural basis for therapeutic inhibition of complement C5.
Matthijs M Jore1, Steven Johnson1, Devon Sheppard1
1Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Nature Structural & Molecular Biology
|March 29, 2016
Summary
Researchers discovered novel tick-derived inhibitors of complement C5 (C5). These inhibitors bind to distinct sites on C5, preventing its activation and offering new therapeutic strategies for complement-mediated diseases.
Area of Science:
- Biochemistry
- Immunology
- Structural Biology
Background:
- Complement C5 activation produces C5a, driving inflammation and cell damage.
- C5 inhibition shows therapeutic promise, exemplified by eculizumab, but its activation mechanism is unclear.
- Understanding C5 activation is crucial for developing new C5-targeted therapeutics.
Purpose of the Study:
- To identify and characterize novel C5 inhibitors.
- To elucidate the mechanism of C5 activation by C5 convertases.
- To explore new therapeutic strategies for C5-mediated conditions.
Main Methods:
- Identification and characterization of tick-derived C5 inhibitors.
- Structural analysis of C5 in complex with inhibitors (OmCI, eculizumab Fab) using X-ray crystallography.
- Biochemical assays to assess C5 convertase inhibition.
Main Results:
- Discovery of a new family of tick-derived C5 inhibitors.
- Structural determination revealed three distinct C5 binding sites, all blocking C5 activation.
- Inhibitor binding sites and competitive inhibition challenge existing steric-inhibition models of C5 activation.
Conclusions:
- Tick-derived inhibitors offer a new approach to C5 inhibition.
- The findings suggest a requirement for a priming event in C5 activation, not solely steric hindrance.
- This research opens avenues for novel therapeutics targeting complement system dysregulation.
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