| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Guttman, Miklos Garcia, Natalie K. Cupo, Albert Matsui, Tsutomu Julien, Jean-Philippe Sanders, Rogier W. Wilson, Ian A. Moore, John P. Lee, Kelly K. |
| Description |
Country affiliation: United States Author Affiliation: Guttman M ( Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.); Garcia NK ( Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.); Cupo A ( Weill Medical College of Cornell University, New York, NY 10021, USA.); Matsui T ( Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.); Julien JP ( Department of Integrative Structural and Computational Biology, International AIDS Vaccine Initiative Neutralizing Antibody Center, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.); Sanders RW ( Weill Medical College of Cornell University, New York, NY 10021, USA); Wilson IA ( Department of Integrative Structural and Computational Biology, International AIDS Vaccine Initiative Neutralizing Antibody Center, Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.); Moore JP ( Weill Medical College of Cornell University, New York, NY 10021, USA.); Lee KK ( Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: kklee@uw.edu.) |
| Abstract |
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. |
| File Format |
HTM / HTML |
| ISSN |
09692126 |
| e-ISSN |
18784186 |
| DOI |
10.1016/j.str.2014.05.001 |
| Journal |
Structure |
| Issue Number |
7 |
| Volume Number |
22 |
| Language |
English |
| Publisher |
Elsevier |
| Publisher Date |
2014-07-08 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Discipline Molecular Biology Discipline Biochemistry Discipline Biotechnology Antigens, Cd4 Chemistry Protein Multimerization Protein Structure, Quaternary Env Gene Products, Human Immunodeficiency Virus Metabolism Deuterium Exchange Measurement Glycosylation Hek293 Cells Hiv Envelope Protein Gp120 Hiv Envelope Protein Gp41 Hiv-1 Drug Effects Physiology Mass Spectrometry Models, Molecular Oxalates Pharmacology Piperazines Piperidines Protein Binding Solubility Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Research Support, U.s. Gov't, Non-p.h.s. |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Structural Biology Molecular Biology |
