4KTE

Fab fragment of HIV vaccine-elicited CD4bs-directed antibody, GE148, from non-human primate

4KTE の概要

• エントリーDOI: 10.2210/pdb4kte/pdb
• 関連するPDBエントリー: 4KTD
• 分子名称: GE148 Heavy Chain Fab, GE148 Light Chain Fab, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: antibody affinity, antibody specificity, vaccine elicited antibodies, fab fragment, aids vaccines, immune system
• 由来する生物種: Macaca mulatta (rhesus macaque); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48831.35

構造登録者

Poulsen, C.,Tran, K.,Stanfield, R.,Wyatt, R.T. (登録日: 2013-05-20, 公開日: 2014-02-05, 最終更新日: 2024-11-20)

主引用文献

Tran, K.,Poulsen, C.,Guenaga, J.,de Val Alda, N.,Wilson, R.,Sundling, C.,Li, Y.,Stanfield, R.L.,Wilson, I.A.,Ward, A.B.,Karlsson Hedestam, G.B.,Wyatt, R.T.
Vaccine-elicited primate antibodies use a distinct approach to the HIV-1 primary receptor binding site informing vaccine redesign.
Proc.Natl.Acad.Sci.USA, 111:E738-E747, 2014

PubMed Abstract: HIV-1 neutralization requires Ab accessibility to the functional envelope glycoprotein (Env) spike. We recently reported the isolation of previously unidentified vaccine-elicited, CD4 binding site (CD4bs)-directed mAbs from rhesus macaques immunized with soluble Env trimers, indicating that this region is immunogenic in the context of subunit vaccination. To elucidate the interaction of the trimer-elicited mAbs with gp120 and their insufficient interaction with the HIV-1 primary isolate spike, we crystallized the Fab fragments of two mAbs, GE136 and GE148. Alanine scanning of their complementarity-determining regions, coupled with epitope scanning of their epitopes on gp120, revealed putative contact residues at the Ab/gp120 interface. Docking of the GE136 and GE148 Fabs to gp120, coupled with EM reconstructions of these nonbroadly neutralizing mAbs (non-bNAbs) binding to gp120 monomers and EM modeling to well-ordered trimers, suggested Ab approach to the CD4bs by a vertical angle of access relative to the more lateral mode of interaction used by the CD4bs-directed bNAbs VRC01 and PGV04. Fitting the structures into the available cryo-EM native spike density indicated clashes between these two vaccine-elicited mAbs and the topside variable region spike cap, whereas the bNAbs duck under this quaternary shield to access the CD4bs effectively on primary HIV isolates. These results provide a structural basis for the limited neutralizing breadth observed by current vaccine-induced, CD4bs-directed Abs and highlight the need for better ordered trimer immunogens. The analysis presented here therefore provides valuable information to guide HIV-1 vaccine immunogen redesign.

PubMed: 24550318
DOI: 10.1073/pnas.1319512111

実験手法

X-RAY DIFFRACTION (1.8 Å)