6VI0

Cryo-EM structure of VRC01.23 in complex with HIV-1 Env BG505 DS.SOSIP

Summary for 6VI0

• Entry DOI: 10.2210/pdb6vi0/pdb
• EMDB information: 21208
• Descriptor: Envelope glycoprotein gp41, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• Functional Keywords: cd4, hiv-1, sosip, vaccine, immune system
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 12
• Total formula weight: 383728.40

Authors

Gorman, J.,Kwong, P.D. (deposition date: 2020-01-10, release date: 2021-01-13, Last modification date: 2024-11-06)

Primary citation

Kwon, Y.D.,Asokan, M.,Gorman, J.,Zhang, B.,Liu, Q.,Louder, M.K.,Lin, B.C.,McKee, K.,Pegu, A.,Verardi, R.,Yang, E.S.,Program, V.P.,Carlton, K.,Doria-Rose, N.A.,Lusso, P.,Mascola, J.R.,Kwong, P.D.
A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention.
Mabs, 13:1946918-1946918,

PubMed Abstract: Passive transfer of broadly neutralizing antibodies is showing promise in the treatment and prevention of HIV-1. One class of antibodies, the VRC01 class, appears especially promising. To improve VRC01-class antibodies, we combined structure-based design with a matrix-based approach to generate VRC01-class variants that filled an interfacial cavity, used diverse third-complementarity-determining regions, reduced potential steric clashes, or exploited extended contacts to a neighboring protomer within the envelope trimer. On a 208-strain panel, variant VRC01.23LS neutralized 90% of the panel at a geometric mean IC less than 1 μg/ml, and in transgenic mice with human neonatal-Fc receptor, the serum half-life of VRC01.23LS was indistinguishable from that of the parent VRC01LS, which has a half-life of 71 d in humans. A cryo-electron microscopy structure of VRC01.23 Fab in complex with BG505 DS-SOSIP.664 Env trimer determined at 3.4-Å resolution confirmed the structural basis for its ~10-fold improved potency relative to VRC01. Another variant, VRC07-523-F54-LS.v3, neutralized 95% of the 208-isolated panel at a geometric mean IC of less than 1 μg/ml, with a half-life comparable to that of the parental VRC07-523LS. Our matrix-based structural approach thus enables the engineering of VRC01 variants for HIV-1 therapy and prevention with improved potency, breadth, and pharmacokinetics.

PubMed: 34328065
DOI: 10.1080/19420862.2021.1946918

Experimental method

ELECTRON MICROSCOPY (3.43 Å)