Microsecond dynamics control the HIV-1 Envelope conformation

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 experiment...

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Bibliographic Details
Published in:Science advances 2024-02, Vol.10 (5), p.eadj0396-eadj0396
Main Authors: Bennett, Ashley L, Edwards, Robert, Kosheleva, Irina, Saunders, Carrie, Bililign, Yishak, Williams, Ashliegh, Bubphamala, Pimthada, Manosouri, Katayoun, Anasti, Kara, Saunders, Kevin O, Alam, S Munir, Haynes, Barton F, Acharya, Priyamvada, Henderson, Rory
Format: Article
Language:English
Subjects:
env Gene Products, Human Immunodeficiency Virus - chemistry
HIV Antibodies
HIV-1
Molecular Conformation
Protein Conformation
Protein Multimerization
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Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adj0396