Zhou, Tongqing;
Chen, Lei;
Gorman, Jason;
Wang, Shuishu;
Kwon, Young D;
Lin, Bob C;
Louder, Mark K;
... Kwong, Peter D; + view all
(2022)
Structural basis for llama nanobody recognition and neutralization of HIV-1 at the CD4-binding site.
Structure
, 30
(6)
862-875.e4.
10.1016/j.str.2022.03.012.
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Abstract
Nanobodies can achieve remarkable neutralization of genetically diverse pathogens, including HIV-1. To gain insight into their recognition, we determined crystal structures of four llama nanobodies (J3, A12, C8, and D7), all of which targeted the CD4-binding site, in complex with the HIV-1 envelope (Env) gp120 core, and determined a cryoelectron microscopy (cryo-EM) structure of J3 with the Env trimer. Crystal and cryo-EM structures of J3 complexes revealed this nanobody to mimic binding to the prefusion-closed trimer for the primary site of CD4 recognition as well as a secondary quaternary site. In contrast, crystal structures of A12, C8, and D7 with gp120 revealed epitopes that included portions of the gp120 inner domain, inaccessible on the prefusion-closed trimer. Overall, these structures explain the broad and potent neutralization of J3 and limited neutralization of A12, C8, and D7, which utilized binding modes incompatible with the neutralization-targeted prefusion-closed conformation of Env.
Type: | Article |
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Title: | Structural basis for llama nanobody recognition and neutralization of HIV-1 at the CD4-binding site |
Location: | United States |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1016/j.str.2022.03.012 |
Publisher version: | https://doi.org/10.1016/j.str.2022.03.012 |
Language: | English |
Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
Keywords: | CD4-binding site, HIV, cryo-EM, crystal structure, envelope trimer, llama VHH, nanobody, neutralization, single-domain antibody, steric clash |
UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
URI: | https://discovery.ucl.ac.uk/id/eprint/10150797 |
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