Malladi, SK and Schreiber, D and Pramanick, I and Sridevi, MA and Goldenzweig, A and Dutta, S and Fleishman, SJ and Varadarajan, R (2020) One-step sequence and structure-guided optimization of HIV-1 envelope gp140. In: Current Research in Structural Biology, 2 . pp. 45-55.
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Abstract
Stabilization of the metastable envelope glycoprotein (Env) of HIV-1 is hypothesized to improve induction of broadly neutralizing antibodies. We improved the expression yield and stability of the HIV-1 envelope glycoprotein BG505SOSIP.664 gp140 by means of a previously described automated sequence and structure-guided computational thermostabilization approach, PROSS. This combines sequence conservation information with computational assessment of mutant stabilization, thus taking advantage of the extensive natural sequence variation present in HIV-1 Env. PROSS is used to design three gp140 variants with 17–45 mutations relative to the parental construct. One of the designs is experimentally observed to have a fourfold improvement in yield and a 4 °C increment in thermostability. In addition, the designed immunogens have similar antigenicity profiles to the native flexible linker version of wild type, BG505SOSIP.664 gp140 (NFL Wt) to major epitopes targeted by broadly neutralizing antibodies. PROSS eliminates the laborious process of screening many variants for stability and functionality, providing a proof of principle of the method for stabilization and improvement of yield without compromising antigenicity for next generation complex, highly glycosylated vaccine candidates. © 2020
| Item Type: | Journal Article |
|---|---|
| Publication: | Current Research in Structural Biology |
| Publisher: | Elsevier B.V. |
| Additional Information: | The copyright for this article belongs to The Author(s). |
| Keywords: | glycoprotein gp 140; neutralizing antibody, algorithm; amino acid sequence; antigenicity; Article; complex formation; controlled study; gene mutation; genetic variability; glycosylation; Human immunodeficiency virus 1; nonhuman; priority journal; process optimization; PROSS protein stability design algorithm; protein function; protein stability; protein structure; sequence analysis; thermostability; wild type |
| Department/Centre: | Division of Biological Sciences > Molecular Biophysics Unit |
| Date Deposited: | 10 Jan 2023 09:20 |
| Last Modified: | 10 Jan 2023 09:20 |
| URI: | https://eprints.iisc.ac.in/id/eprint/79014 |
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