Journal
STRUCTURE
Volume 22, Issue 7, Pages 974-984Publisher
CELL PRESS
DOI: 10.1016/j.str.2014.05.001
Keywords
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Funding
- NIH [F32-GM097805, T32-GM007750, R00-GM080352, R01-GM099989, P01-AI82362, R01-AI084817, R37-AI36082, R01-AI41420]
- Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery [OPP1033102]
- University of Alabama at Birmingham's Center for AIDS Research through the Creative and Novel Ideas in HIV Research program for new HIV investigators [P30-AI027767]
- International AIDS Vaccine Initiative Neutralizing Antibody Consortium and Center
- Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery [UM1 AI100663]
- Hope Barns Fellowship
- Netherlands Organization for Scientific Research
- Starting Investigator Grant from the European Research Council [ERC-StG-2011-280829-SHEV]
- Canadian Institutes of Health Research fellowship
- Department of Energy's Office of Biological and Environmental Research
- NIH's National Institute of General Medical Sciences [P41-GM103393]
- National Center for Research Resources [P41-RR001209]
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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.
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