Streptococcus pyogenes is responsible for a wide variety of human diseases ranging from minor skin infections and pharyngitis to more serious complications such as rheumatic fever and flesh-eating disease. The varying degrees of pathogenicity observed between different strains of S. pyogenes are largely due to the expression of prophage encoded toxins and virulence factors. Furthermore, these toxin and virulence genes are actively spread between different strains and species of Streptococcus by horizontal gene transfer. One important mechanism of horizontal gene transfer in Streptococcus is natural transformation, which involves the uptake of exogenous DNA. This processes is regulated by either the ComRS or ComCDE quorum sensing pathways. S. pyogenes contains the ComRS quorum sensing system, which is negatively regulated by a phage protein paratox (Prx). Prx is a small conserved protein that is encoded at the 3’ end of the prophage, directly adjacent to a toxin or virulence gene. However, little was known about the global role of Prx in the biology of the phage or its detailed mechanism of natural competence inhibition. An X-ray crystal structure reveals that Prx binds directly to the DNA binding domain of the transcription factor ComR. Additional biochemical assays also show that Prx functions by directly preventing DNA binding without affecting signal peptide (XIP) recognition. Thus, Prx is able to interact with ComR in either the apo (inactive) conformation and the XIP bound (active) conformation. This mechanism of quorum sensing inhibition, while structurally unique, is analogous to the quorum sensing repression observed by a Pseudomonas aeruginosa phage protein, Aqs1. While the inhibition of natural competence expression could be beneficial to prophage, it is also hypothesized that Prx may play an additional biological role. To address this hypothesis, pull-down assays with S. pyogenes lysates were performed and revealed a number of additional putative Prx binding partners worth further investigation.