Evaluation of: Tran EE, Borgnia MJ, Kybeda O et al. Structural mechanism of trimeric HIV-1 envelope glycoprotein activation. PLoS Pathog. 8(7), e1002797 (2012). New breakthroughs are needed in the ongoing struggle to develop an effective HIV vaccine. Chief among the challenges to obtaining an effective vaccine is the remarkable ability of the virus to evade humoral immune responses that arise in the infected host. Understanding how broadly neutralizing antibodies directed against the trimeric envelope glycoprotein of HIV (Env) work to overcome viral defenses is, therefore, a high priority. Tran and colleagues used high-resolution 3D cryoelectron tomography to define the conformation of Env when bound to soluble CD4 and to a series of monoclonal antibodies. The investigators demonstrate that antibodies binding to the CD4 binding site or coreceptor binding site of Env may lead to significantly different conformations of the trimeric Env complex. Remarkably, the broadly neutralizing antibody VRC01 locks the complex in a closed conformation, while binding to soluble CD4 or the monoclonal antibody 17b fixed the trimer in an open conformation. Furthermore, these investigators were able to define a new open conformation of the N-terminal region of the gp41 transmembrane protein, which is proposed to be a new structural intermediate occurring after receptor engagement. These findings may aid in the design of immunogens that can generate broadly neutralizing antibodies against HIV-1.