Structure and Interactions of HIV-1 gp41 CHR-NHR Reverse Hairpin Constructs Reveal Molecular Determinants of Antiviral Activity

He, Li; McAndrew, Ryan; Barbu, Razvan; Gifford, Grant; Halacoglu, Cari; Drouin-Allaire, Camille; Weber, Lindsey; Kristensen, Line G.; Gupta, Sayan; Chen, Yan; Petzold, Christopher J.; Allaire, Marc; Li, Kathy H.; Ralston, Corie Y.; Gochin, Miriam

doi:10.1016/j.jmb.2024.168650

Title: Structure and Interactions of HIV-1 gp41 CHR-NHR Reverse Hairpin Constructs Reveal Molecular Determinants of Antiviral Activity

Journal Article · Mon Jun 10 00:00:00 UTC 2024 · Journal of Molecular Biology

DOI: https://doi.org/10.1016/j.jmb.2024.168650 · OSTI ID:2467431

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^[1]; Gifford, Grant ^[1];

^[1]; Drouin-Allaire, Camille ^[2];

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^[2]; Gupta, Sayan ^[2];

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^[2]; Li, Kathy H. ^[3];

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Touro University, Vallejo, CA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
University of California, San Francisco, CA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Molecular Foundry
Touro University, Vallejo, CA (United States); University of California, San Francisco, CA (United States)

Engineered reverse hairpin constructs containing a partial C-heptad repeat (CHR) sequence followed by a short loop and full-length N-heptad repeat (NHR) were previously shown to form trimers in solution and to be nanomolar inhibitors of HIV-1 Env mediated fusion. Their target is the in situ gp41 fusion intermediate, and they have similar potency to other previously reported NHR trimers. However, their design implies that the NHR is partially covered by CHR, which would be expected to limit potency. An exposed hydrophobic pocket in the folded structure may be sufficient to confer the observed potency, or they may exist in a partially unfolded state exposing full length NHR. Here, in this study, we examined their structure by crystallography, CD and fluorescence, establishing that the proteins are folded hairpins both in crystal form and in solution. We examined unfolding in the milieu of the fusion reaction by conducting experiments in the presence of a membrane mimetic solvent and by engineering a disulfide bond into the structure to prevent partial unfolding. We further examined the role of the hydrophobic pocket, using a hairpin-small molecule adduct that occluded the pocket, as confirmed by X-ray footprinting. The results demonstrated that the NHR region nominally covered by CHR in the engineered constructs and the hydrophobic pocket region that is exposed by design were both essential for nanomolar potency and that interaction with membrane is likely to play a role in promoting the required inhibitor structure. The design concepts can be applied to other Class 1 viral fusion proteins.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2467431

Journal Information:: Journal of Molecular Biology, Journal Name: Journal of Molecular Biology Journal Issue: 16 Vol. 436; ISSN 0022-2836

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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