Published February 2, 2024
| Version v1
Journal article
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Microsecond dynamics control the HIV-1 Envelope conformation
Creators
- 1. Duke University Medical Center
- 2. University of Chicago
Description
The HIV-1 Envelope (Env) glycoprotein facilitates host cell fusion through a complex series of receptor-induced structural changes. Although remarkable progress has been made in understanding the structures of various Env conformations, microsecond timescale dynamics have not been studied experimentally. Here, we used time-resolved, temperature-jump small-angle x-ray scattering to monitor structural rearrangements in an HIV-1 Env SOSIP ectodomain construct with microsecond precision. In two distinct Env variants, we detected a transition that correlated with known Env structure rearrangements with a time constant in the hundreds of microseconds range. A previously unknown structural transition was also observed, which occurred with a time constant below 10 μs, and involved an order-to-disorder transition in the trimer apex. Using this information, we engineered an Env SOSIP construct that locks the trimer in the prefusion closed state by connecting adjacent protomers via disulfides. Our findings show that the microsecond timescale structural dynamics play an essential role in controlling the Env conformation with impacts on vaccine design.
Data availability
All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Cryo-EM reconstructions and atomic models have been deposited in the EMDB and wwPDB with accession codes 8SXI and 8SXJ and EMD-40854 and EMD-40853. The SAXS data, including processed SAXS curves, have been deposited to the SASBDB with accession codes SASDTZ9, SASDU22, SASDU32, SASDU42, SASDTX9, SASDTY9 for the CH505 transmitted founder, CH505 variants isolated at weeks 53, 78, and 100 post-infection, a 4.1 stabilized CH505 transmitted founder, and the BG505 Env SOSIP panel, SASDT29, SASDT39, SASDT49, SASDT59 for the CH505 temperature series static data, SASDT69, SASDT79, SASDT89, SASDT99, SASDTA9, SASDTB9, SASDTC9, SASDTD9, SASDTE9, SASDTF9, SASDTG9 for CH505 T-Jump data, SASDTH9, SASDTJ9, SASDTK9, SASDTL9 for the CH848 temperature series static data, and SASDTM9, SASDTN9, SASDTP9, SASDTQ9, SASDTR9, SASDTS9, SASDTT9, SASDTU9, SASDTV9, SASDTW9 for CH848 T-Jump data. The code used to process and analyze the SAXS data is available on GitLab: https://gitlab.oit.duke.edu/tr_t-jump_saxs/y22-23, doi:10.5281/zenodo.10424314. Filtered molecular dynamics trajectories are available on Zenodo (10.5281/zenodo.10451687).
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Additional details
Identifiers
- DOI
- 10.1126/sciadv.adj0396
- Other
- oai:uchicago.tind.io:11101
Funding
- National Institutes of Health
- P30 GM124169
- U.S. Department of Energy
- DE-AC02-06CH11357
- National Institute of General Medical Sciences
- P41 GM118217
- National Institute of Allergy and Infectious Diseases
- UM1AI144371
- National Institute of Allergy and Infectious Diseases
- R01AI145687
- National Institute of Allergy and Infectious Diseases
- U54AI170752
- High-End Instrumentation Grant
- S10OD018483
- Translating Duke Health Initiative