8VWE

HIV-1 neutralizing antibody D5_AR bound to HIV-1 gp41 coiled-coil pocket IQN17

Summary for 8VWE

• Entry DOI: 10.2210/pdb8vwe/pdb
• Descriptor: Neutralizing antibody D5_AR Heavy Chain, Transmembrane protein gp41 IQN17 peptide, Neutralizing antibody D5_AR Light Chain, ... (4 entities in total)
• Functional Keywords: hiv-1 fusion inhibitor, gp41, hiv-1 neutralizing antibody, prehairpin intermediate, viral protein, viral protein-immune system complex, viral protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 52073.56

Authors

Filsinger Interrante, M.V.,Tang, S.,Fernandez, D.,Kim, P.S. (deposition date: 2024-02-01, release date: 2025-07-02, Last modification date: 2025-07-30)

Primary citation

Filsinger Interrante, M.V.,Tang, S.,Kim, S.,Shanker, V.R.,Hie, B.L.,Bruun, T.U.J.,Wu, W.,Pak, J.E.,Fernandez, D.,Kim, P.S.
Utilizing Machine Learning to Improve Neutralization Potency of an HIV-1 Antibody Targeting the gp41 N-Heptad Repeat.
Acs Chem.Biol., 20:1470-1480, 2025

PubMed Abstract: The N-heptad repeat (NHR) of the HIV-1 gp41 prehairpin intermediate (PHI) is an attractive potential vaccine target with high sequence conservation across diverse strains. However, despite the potency of NHR-targeting peptides and clinical efficacy of the NHR-targeting entry inhibitor enfuvirtide, no potently neutralizing NHR-directed monoclonal antibodies (mAbs) nor antisera have been identified or elicited to date. The lack of potent NHR-binding mAbs both dampens enthusiasm for vaccine development efforts at this target and presents a barrier to performing passive immunization experiments with NHR-targeting antibodies. To address this challenge, we previously developed an improved variant of the NHR-directed mAb D5, called D5_AR, which is capable of neutralizing diverse tier-2 viruses. Building on that work, here we present the 2.7Å-crystal structure of D5_AR bound to NHR mimetic peptide IQN17. We then utilize protein language models and supervised machine learning to generate small ( < 100) libraries of D5_AR variants that are subsequently screened for improved neutralization potency. We identify a variant with 5-fold improved neutralization potency, D5_FI, which is the most potent NHR-directed monoclonal antibody characterized to date and exhibits broad neutralization of tier-2 and -3 pseudoviruses as well as replicating R5 and X4 challenge strains. Additionally, our work highlights the ability of protein language models to efficiently identify improved mAb variants from relatively small libraries.

PubMed: 40540236
DOI: 10.1021/acschembio.5c00035

Experimental method

X-RAY DIFFRACTION (2.2 Å)