5w6d | pdb_00005w6d
Crystal structure of BG505-SOSIP.v4.1-GT1-N137A in complex with Fabs 35022 and 9H/109L
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 PubMedInduction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOSIP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOSIP.v4.1-GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resulting in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-A resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors. Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo.,Medina-Ramirez M, Garces F, Escolano A, Skog P, de Taeye SW, Del Moral-Sanchez I, McGuire AT, Yasmeen A, Behrens AJ, Ozorowski G, van den Kerkhof TLGM, Freund NT, Dosenovic P, Hua Y, Gitlin AD, Cupo A, van der Woude P, Golabek M, Sliepen K, Blane T, Kootstra N, van Breemen MJ, Pritchard LK, Stanfield RL, Crispin M, Ward AB, Stamatatos L, Klasse PJ, Moore JP, Nemazee D, Nussenzweig MC, Wilson IA, Sanders RW J Exp Med. 2017 Sep 4;214(9):2573-2590. doi: 10.1084/jem.20161160. Epub 2017 Aug , 28. PMID:28847869[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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