8flw

From Proteopedia

Cryo-EM Structure of PGT145 DU303 Fab in complex with BG505 DS-SOSIP.664

Structural highlights

8flw is a 8 chain structure with sequence from Homo sapiens and Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.58Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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) against HIV can reduce viral transmission in humans, but an effective therapeutic will require unusually high breadth and potency of neutralization. We employ the OSPREY computational protein design software to engineer variants of two apex-directed bNAbs, PGT145 and PG9RSH, resulting in increases in potency of over 100-fold against some viruses. The top designed variants improve neutralization breadth from 39% to 54% at clinically relevant concentrations (IC(80) < 1 mug/mL) and improve median potency (IC(80)) by up to 4-fold over a cross-clade panel of 208 strains. To investigate the mechanisms of improvement, we determine cryoelectron microscopy structures of each variant in complex with the HIV envelope trimer. Surprisingly, we find the largest increases in breadth to be a result of optimizing side-chain interactions with highly variable epitope residues. These results provide insight into mechanisms of neutralization breadth and inform strategies for antibody design and improvement.

Improved HIV-1 neutralization breadth and potency of V2-apex antibodies by in silico design.,Holt GT, Gorman J, Wang S, Lowegard AU, Zhang B, Liu T, Lin BC, Louder MK, Frenkel MS, McKee K, O'Dell S, Rawi R, Shen CH, Doria-Rose NA, Kwong PD, Donald BR Cell Rep. 2023 Jul 25;42(7):112711. doi: 10.1016/j.celrep.2023.112711. Epub 2023 , Jul 11. PMID:37436900^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Holt GT, Gorman J, Wang S, Lowegard AU, Zhang B, Liu T, Lin BC, Louder MK, Frenkel MS, McKee K, O'Dell S, Rawi R, Shen CH, Doria-Rose NA, Kwong PD, Donald BR. Improved HIV-1 neutralization breadth and potency of V2-apex antibodies by in silico design. Cell Rep. 2023 Jul 25;42(7):112711. PMID:37436900 doi:10.1016/j.celrep.2023.112711