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Molecular structures of trimeric HIV-1 Env in complex with small antibody derivatives.

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Meyerson JR, Tran EE, Kuybeda O, Chen W, Dimitrov DS, Gorlani A, Verrips T, Lifson JD, Subramaniam S
Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):513-8. doi: 10.1073/pnas.1214810110. Epub 2012 Dec 24.
Abstract: 

The extensive carbohydrate coat, the variability of protein structural features on HIV-1 envelope glycoproteins (Env), and the steric constraints of the virus-cell interface during infection, present challenges to the elicitation of effective full-length (~150 kDa), neutralizing antibodies against HIV. These hurdles have motivated the engineering of smaller antibody derivatives that can bind Env and neutralize the virus. To further understand the mechanisms by which these proteins neutralize HIV-1, we carried out cryoelectron tomography of native HIV-1 BaL virions complexed separately to two small (~15 kDa) HIV-neutralizing proteins: A12, which binds the CD4-binding site on Env, and m36, whose binding to Env is enhanced by CD4 binding. We show that despite their small size, the presence of these proteins and their effects on the quaternary conformation of trimeric Env can be visualized in molecular structures derived by cryoelectron tomography combined with subvolume averaging. Binding of Env to A12 results in a conformational change that is comparable to changes observed upon its binding to the CD4-binding site antibody, b12. In contrast, binding of Env to m36 results in an "open" quaternary conformation similar to that seen with binding of soluble CD4 or the CD4i antibody, 17b. Because these small neutralizing proteins are less sterically hindered than full-length antibodies at zones of virus-cell contact, the finding that their binding has the same structural consequences as that of other broadly neutralizing antibodies highlights their potential for use in therapeutic applications.

Meyerson JR, Tran EE, Kuybeda O, Chen W, Dimitrov DS, Gorlani A, Verrips T, Lifson JD, Subramaniam S. Molecular structures of trimeric HIV-1 Env in complex with small antibody derivatives. Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):513-8. doi: 10.1073/pnas.1214810110. Epub 2012 Dec 24.