Solution structure, conformational dynamics, and CD4-induced activation in full-length, glycosylated, monomeric HIV gp120.
The gp120 subunit of the HIV Env glycoprotein is responsible for receptor interactions leading to viral entry and is a primary target for neutralizing antibodies. Most structural studies have focused on the heavily truncated, deglycosylated gp120 core, leaving fundamental aspects of the glycoprotein that are responsible for immune evasion and receptor-induced activation unresolved. Here we investigate full-length, glycosylated HIV gp120 in unliganded and CD4-bound forms by using small-angle X-ray scattering to visualize global structural reorganization and hydrogen/deuterium exchange to track changes in local conformational dynamics. The studies revealed unliganded full-length gp120 to be considerably more dynamic, particularly at the CD4 binding site, than suggested by previous studies of the subunit core alone. The large V1/V2 loops, previously unmapped, are positioned to mask the coreceptor binding site in an orientation that recapitulates that observed in the Env trimer. CD4 binding shifts V1/V2 to unmask the coreceptor binding site and triggers profound dynamic changes in gp120 spanning from the binding site to the gp41-interactive face of gp120. These findings provide further insights on the structural basis of Env antigenicity and immunogenicity and of allosteric effects upon receptor binding.
Department of Medicinal Chemistry, University of Washington, Seattle, Washington, USA.
Miklos
M
Guttman
Maria
M
Kahn
Natalie K
NK
Garcia
Shiu-Lok
SL
Hu
Kelly K
KK
Lee
D015704:CD4 Antigens / Q000737:chemistry* / Q000378:metabolism*; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D053838:Scattering, Small Angle
D015704:CD4 Antigens; D006023:Glycoproteins; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1