CD4-induced activation in a soluble HIV-1 Env trimer

Structure. 2014 Jul 8;22(7):974-84. doi: 10.1016/j.str.2014.05.001. Epub 2014 Jun 12.


The HIV envelope glycoprotein (Env) trimer undergoes receptor-induced conformational changes that drive fusion of the viral and cellular membranes. Env conformational changes have been observed using low-resolution electron microscopy, but only large-scale rearrangements have been visible. Here, we use hydrogen-deuterium exchange and oxidative labeling to gain a more precise understanding of the unliganded and CD4-bound forms of soluble Env trimers (SOSIP.664), including their glycan composition. CD4 activation induces the reorganization of bridging sheet elements, V1/V2 and V3, much of the gp120 inner domain, and the gp41 fusion subunit. Two CD4 binding site-targeted inhibitors have substantially different effects: NBD-556 partially mimics CD4-induced destabilization of the V1/V2 and V3 crown, whereas BMS-806 only affects regions around the gp120/gp41 interface. The structural information presented here increases our knowledge of CD4- and small molecule-induced conformational changes in Env and the allosteric pathways that lead to membrane fusion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • CD4 Antigens / chemistry*
  • CD4 Antigens / metabolism
  • Deuterium Exchange Measurement
  • Glycosylation
  • HEK293 Cells
  • HIV Envelope Protein gp120 / chemistry
  • HIV Envelope Protein gp120 / metabolism
  • HIV Envelope Protein gp41 / chemistry
  • HIV Envelope Protein gp41 / metabolism
  • HIV-1 / drug effects
  • HIV-1 / metabolism
  • HIV-1 / physiology
  • Humans
  • Mass Spectrometry / methods
  • Models, Molecular
  • Oxalates / chemistry
  • Oxalates / metabolism
  • Oxalates / pharmacology
  • Piperazines / chemistry
  • Piperazines / metabolism
  • Piperazines / pharmacology
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Piperidines / pharmacology
  • Protein Binding / drug effects
  • Protein Multimerization*
  • Protein Structure, Quaternary*
  • Solubility
  • env Gene Products, Human Immunodeficiency Virus / chemistry*
  • env Gene Products, Human Immunodeficiency Virus / metabolism


  • BMS 806
  • CD4 Antigens
  • HIV Envelope Protein gp120
  • HIV Envelope Protein gp41
  • N-(4-chlorophenyl)-N'-(2,2,6,6-tetramethylpiperidin-4-yl)oxalamide
  • Oxalates
  • Piperazines
  • Piperidines
  • env Gene Products, Human Immunodeficiency Virus