Real-time Exchange of the Lipid-bound Intermediate and Post-fusion States of the HIV-1 gp41 Ectodomain |
| |
| Affiliation: | 1. Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, United Kingdom;2. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, United States;1. Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, Kentucky, USA;2. Department of Microbiology, Immunology, and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, Kentucky, USA;3. Departments of Medicinal Chemistry and Molecular Pharmacology and of Chemistry, Purdue Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA;1. School of Pharmacy, University of Nottingham, East Drive, University Park, Nottingham NG7 2RD, UK;2. Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia;3. Leicester Institute of Structural & Chemical Biology and Department of Molecular & Cell Biology, University of Leicester, Leicester LE1 7RH, UK;1. Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel;2. Department of Biochemistry and Molecular Biology, Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, United States;1. College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou 341000, China;2. School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China;3. Shenzhen Crystalo Biopharmaceutical Co., Ltd, Shenzhen 518118, China;4. Jiangxi Jmerry Biopharmaceutical Co., Ltd, Ganzhou 341000, China;5. Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom;1. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK;2. Stevenage Bioscience Catalyst, Gunnels Wood Rd, Stevenage SG1 2FX, UK;3. Wolfson Centre for Age-Related Diseases, King’s College London, Guy’s Campus, London Bridge, London SE1 1UL, UK |
| |
| Abstract: | The envelope glycoprotein gp41 of the HIV-1 virus mediates its entry into the host cell. During this process, gp41 undergoes large conformational changes and the energy released in the remodeling events is utilized to overcome the barrier associated with fusing the viral and host membranes. Although the structural intermediates of this fusion process are attractive targets for drug development, no detailed high-resolution structural information or quantitative thermodynamic characterization are available. By measuring the dynamic equilibrium between the lipid-bound intermediate and the post-fusion six-helical bundle (6HB) states of the gp41 ectodomain in the presence of bilayer membrane mimetics, we derived both the reaction kinetics and energies associated with these two states by solution NMR spectroscopy. At equilibrium, an exchange time constant of about 12 seconds at 38 °C is observed, and the post-fusion conformation is energetically more stable than the lipid-bound state by 3.4 kcal mol?1. The temperature dependence of the kinetics indicates that the folding occurs through a high-energy transition state which may resemble a 5HB structure. The energetics and kinetics of gp41 folding in the context of membrane bilayers provide a molecular basis for an improved understanding of viral membrane fusion. |
| |
| Keywords: | class I fusion protein membrane fusion fusion intermediate slow-exchange kinetics gp41 folding |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
