| Structural highlights
Function
[Q2N0S6_9HIV1] The envelope glyprotein gp160 precursor down-modulates cell surface CD4 antigen by interacting with it in the endoplasmic reticulum and blocking its transport to the cell surface (By similarity).[RuleBase:RU004292][SAAS:SAAS000328_004_020447] The gp120-gp41 heterodimer allows rapid transcytosis of the virus through CD4 negative cells such as simple epithelial monolayers of the intestinal, rectal and endocervical epithelial barriers. Both gp120 and gp41 specifically recognize glycosphingolipids galactosyl-ceramide (GalCer) or 3' sulfo-galactosyl-ceramide (GalS) present in the lipid rafts structures of epithelial cells. Binding to these alternative receptors allows the rapid transcytosis of the virus through the epithelial cells. This transcytotic vesicle-mediated transport of virions from the apical side to the basolateral side of the epithelial cells does not involve infection of the cells themselves (By similarity).[SAAS:SAAS000328_004_240990]
Publication Abstract from PubMed
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.
Improvement of antibody functionality by structure-guided paratope engraftment.,Liu Q, Lai YT, Zhang P, Louder MK, Pegu A, Rawi R, Asokan M, Chen X, Shen CH, Chuang GY, Yang ES, Miao H, Wang Y, Fauci AS, Kwong PD, Mascola JR, Lusso P Nat Commun. 2019 Feb 13;10(1):721. doi: 10.1038/s41467-019-08658-4. PMID:30760721[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Liu Q, Lai YT, Zhang P, Louder MK, Pegu A, Rawi R, Asokan M, Chen X, Shen CH, Chuang GY, Yang ES, Miao H, Wang Y, Fauci AS, Kwong PD, Mascola JR, Lusso P. Improvement of antibody functionality by structure-guided paratope engraftment. Nat Commun. 2019 Feb 13;10(1):721. doi: 10.1038/s41467-019-08658-4. PMID:30760721 doi:http://dx.doi.org/10.1038/s41467-019-08658-4
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