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Structural basis for llama nanobody recognition and neutralization of HIV-1 at the CD4-binding site

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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McCoy_Manuscript_STRUCTURE-D-21-00220_R3_2022-03-11.pdf - Accepted Version
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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
Title: Structural basis for llama nanobody recognition and neutralization of HIV-1 at the CD4-binding site
Location: United States
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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