The causative agent of dengue fever, dengue hemorrhagic fever and dengue shock syndrome, DENV has emerged in the past several decades as the most important mosquito borne viral disease with an estimated 2.5 billion people living in areas at risk for epidemic transmission and 50-100 million people infected annually [25, 26] . Complicating this situation, the four distinct serotypes of DENV generate only low level immunological cross protection, allowing for repeated epidemic outbreaks in the same populations [27, 28] . The phenomenon of antibody dependent enhancement has been shown to result in more severe disease in individuals who have been previously infected with a different serotype [29] [30] [31] [32] [33] . With no specific treatment or prevention available other than vector control, DENV is an important target for the development of antivirals and vaccines. The results presented here indicate that the DENV E glycoprotein has multiple accessible surfaces that can be targeted by distinct inhibitors and is an amenable target for rational inhibitor design.