6NM6

Crystal Structure of HIV-1 BG505 SOSIP.664 Prefusion Env Trimer Bound to N6 FR3-03 scFv in Complex with Crystallization Chaperones 3H109L Fab and 35O22 scFv at 3.2 Angstrom

Summary for 6NM6

• Entry DOI: 10.2210/pdb6nm6/pdb
• Descriptor: Envelope glycoprotein gp41, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (15 entities in total)
• Functional Keywords: hiv-1 envelope prefusion trimer, cd4-binding site antibodies, chimeric antibodies, immune system
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 8
• Total formula weight: 188558.35

Authors

Lai, Y.-T.,Kwong, P.D. (deposition date: 2019-01-10, release date: 2019-02-27, Last modification date: 2024-11-13)

Primary citation

Liu, Q.,Lai, Y.T.,Zhang, P.,Louder, M.K.,Pegu, A.,Rawi, R.,Asokan, M.,Chen, X.,Shen, C.H.,Chuang, G.Y.,Yang, E.S.,Miao, H.,Wang, Y.,Fauci, A.S.,Kwong, P.D.,Mascola, J.R.,Lusso, P.
Improvement of antibody functionality by structure-guided paratope engraftment.
Nat Commun, 10:721-721, 2019

PubMed Abstract: Broadly neutralizing antibodies (bNAbs) represent a promising alternative to antiretroviral drugs for HIV-1 prevention and treatment. Selected antibodies to the CD4-binding site bolster envelope trimer binding via quaternary contacts. Here, we rationally engraft a new paratope, i.e., the extended heavy-chain framework region 3 (FR3) loop of VRC03, which mediates quaternary interaction, onto several potent bNAbs, enabling them to reach an adjacent gp120 protomer. The interactive quaternary surface is delineated by solving the crystal structure of two FR3 loop-chimeric antibodies. Chimerization enhances the neutralizing activity of several potent bNAbs against a majority of global HIV-1 strains. Compared to unmodified antibodies, chimeric antibodies display lower autoreactivity and prolonged in vivo half-life in huFcRn mice and rhesus macaques. Thus, paratope engraftment may be used to expand the epitope repertory of natural antibodies, improving their functionality for disease prevention and treatment.

PubMed: 30760721
DOI: 10.1038/s41467-019-08658-4

Experimental method

X-RAY DIFFRACTION (2.739 Å)