An inhibitor of complement C5 provides structural insights into activation

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• The complement system is a key component of innate immunity, essential for pathogen defense.
• Ticks, like *Rhipicephalus pulchellus*, require mechanisms to evade host immune responses during prolonged feeding.
• Tick saliva contains} inhibitors that counteract host defenses, including complement activation.

Purpose of the Study:

• To identify and characterize novel inhibitors of the complement system in *Rhipicephalus pulchellus* tick saliva.
• To elucidate the structural basis and mechanism of action for complement inhibition by tick-derived proteins.
• To gain insights into the regulation of the terminal complement pathway.

Main Methods:

• Identification and purification of the CirpT protein family from tick saliva.
• Cryoelectron microscopy (cryo-EM) to determine the structure of the complement C5-CirpT complex.
• X-ray crystallography to obtain high-resolution structural data of the C5_MG4-CirpT complex (2.7 Å).

Main Results:

• A novel class of complement inhibitors, the CirpT family, was identified in *Rhipicephalus pulchellus* saliva.
• The structure of the C5-CirpT complex revealed that CirpT binds to the C5_MG4 domain of C5.
• Detailed structural analysis elucidated the molecular mechanism by which CirpT inhibits C5 activation.

Conclusions:

• CirpT proteins represent an effective strategy for ticks to suppress the host complement system.
• The structural insights into C5 inhibition by CirpT enhance our understanding of complement regulation.
• This study provides a foundation for exploring novel therapeutic strategies targeting the terminal complement pathway.