Positive selection analyses identify a single WWE domain residue that shapes ZAP into a super restriction factor.

genus. We observed that our mutant ZAP has reduced ability to bind poly(ADP-ribose), a post-translational modification that is targeted by alphaviruses for productive infection. Our findings help us better understand how viruses have shaped the evolution of broad-spectrum host antiviral proteins, with great implications for the engineering of super restriction factors.