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A Co-receptor-mimicking Antibody Stabilizes the Displaced V1V2 Loops in a Partially Open sCD4-bound HIV-1 Envelope Complex

Barnes, Christopher O. and Wang, Haoqing and Yang, Zhi and Nussenzweig, Michel and Bjorkman, Pamela (2018) A Co-receptor-mimicking Antibody Stabilizes the Displaced V1V2 Loops in a Partially Open sCD4-bound HIV-1 Envelope Complex. AIDS Research and Human Retroviruses, 34 (S1). p. 131. ISSN 0889-2229. doi:10.1089/aid.2018.5000.abstracts.

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Background: HIV-1 envelope glycoprotein (Env), a trimer of gp120-gp41 heterodimers, mediates membrane fusion after binding host receptor CD4. Receptor binding to closed Env displaces the V1V2 loops from Env‘s apex, allowing co-receptor binding and opening Env to enable gp41-mediated fusion. Methods: Using single-particle cryoEM methods, we solved the sCD4-bound structure of a clade B B41 SOSIP trimer in complex with 21c, a CD4-induced (CD4i) coreceptor-mimicking antibody, and with 8ANC195, a broadly neutralizing antibody (bNAb) that recognizes the gp120-gp41 interface, to a resolution of 4.05 Å. Results: Despite binding of the 8ANC195 Fab that partially closes the open, sCD4-bound Env conformation, our structure shows rearrangements in gp120, including displacement of V1V2, exposure of V3, formation of the 4-stranded bridging sheet, and formation of the α0 helix. In addition, unlike the V1V2 regions in similar sCD4-bound Env structures complexed with the CD4i antibody 17b, the displaced V1V2 loops in the B41-sCD4-21c-8ANC195 structure exhibited ordered density allowing the structure of the displaced V1V2 to be determined for the first time. Comparing partially- and fully-open Envs with closed Envs shows that gp41 rearrangements are independent of CD4-induced gp120 bridging sheet formation and V1V2 displacement, suggesting an order of conformational changes before co-receptor binding: (i) gp120 opening inducing side chain rearrangements and a compact gp41 central helix conformation, and (ii) bridging sheet formation, and V1V2 displacement. Conclusions: Analyses of these results further our understanding of HIV-1 Env conformational changes leading to fusion and provide templates for designing agents to disrupt HIV-1 entry into target cells.

Item Type:Article
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URLURL TypeDescription
Barnes, Christopher O.0000-0003-2754-5951
Wang, Haoqing0000-0003-0277-3018
Yang, Zhi0000-0001-8680-3784
Nussenzweig, Michel0000-0003-0592-8564
Bjorkman, Pamela0000-0002-2277-3990
Additional Information:© 2018 Mary Ann Liebert, Inc., publishers. Published Online: 22 Oct 2018.
Issue or Number:S1
Record Number:CaltechAUTHORS:20181116-084257854
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90948
Deposited By: Tony Diaz
Deposited On:16 Nov 2018 17:04
Last Modified:16 Nov 2021 03:37

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