|Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures.
|Year of Publication
|Harris A, Borgnia MJ, Shi D, Bartesaghi A, He H, Pejchal R, Kang YKenneth, Depetris R, Marozsan AJ, Sanders RW, Klasse PJohan, Milne JLS, Wilson IA, Olson WC, Moore JP, Subramaniam S
|Proc Natl Acad Sci U S A
|2011 Jul 12
|AIDS Vaccines, Antigens, CD4, Biophysical Phenomena, Cryoelectron Microscopy, env Gene Products, Human Immunodeficiency Virus, HIV Antibodies, HIV Antigens, HIV Envelope Protein gp120, HIV-1, Humans, Immunoglobulin Fab Fragments, Ligands, Models, Molecular, Protein Structure, Quaternary
The initial step in HIV-1 infection occurs with the binding of cell surface CD4 to trimeric HIV-1 envelope glycoproteins (Env), a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120). The design of soluble versions of trimeric Env that display structural and functional properties similar to those observed on intact viruses is highly desirable from the viewpoint of designing immunogens that could be effective as vaccines against HIV/AIDS. Using cryoelectron tomography combined with subvolume averaging, we have analyzed the structure of SOSIP gp140 trimers, which are cleaved, solubilized versions of the ectodomain of trimeric HIV-1 Env. We show that unliganded gp140 trimers adopt a quaternary arrangement similar to that displayed by native unliganded trimers on the surface of intact HIV-1 virions. When complexed with soluble CD4, Fab 17b, which binds to gp120 at its chemokine coreceptor binding site, or both soluble CD4 and 17b Fab, gp140 trimers display an open conformation in which there is an outward rotation and displacement of each gp120 protomer. We demonstrate that the molecular arrangements of gp120 trimers in the closed and open conformations of the soluble trimer are the same as those observed for the closed and open states, respectively, of trimeric gp120 on intact HIV-1 BaL virions, establishing that soluble gp140 trimers can be designed to mimic the quaternary structural transitions displayed by native trimeric Env.
|Proc. Natl. Acad. Sci. U.S.A.
|PubMed Central ID
|45463 / / PHS HHS / United States
AI36082 / AI / NIAID NIH HHS / United States
P01 AI-082362 / AI / NIAID NIH HHS / United States
R01 AI084817 / AI / NIAID NIH HHS / United States
Submitted by alp2017 on January 27, 2015 - 6:56am