8TZW

Crystal structure of 10E8-GT4 scaffold in complex with a human 10E8 inferred germline (10E8-iGL1)

Summary for 8TZW

• Entry DOI: 10.2210/pdb8tzw/pdb
• Descriptor: 10E8-IGL1 Fab heavy chain, 10E8-IGL1 Fab Light Chain, 10E8-GT4 epitope scaffold, ... (4 entities in total)
• Functional Keywords: vaccine, broadly neutralizing antibody, hiv, gp41, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 65174.74

Authors

Irimia, A.,Wilson, I.A. (deposition date: 2023-08-28, release date: 2024-06-12, Last modification date: 2024-10-09)

Primary citation

Schiffner, T.,Phung, I.,Ray, R.,Irimia, A.,Tian, M.,Swanson, O.,Lee, J.H.,Lee, C.D.,Marina-Zarate, E.,Cho, S.Y.,Huang, J.,Ozorowski, G.,Skog, P.D.,Serra, A.M.,Rantalainen, K.,Allen, J.D.,Baboo, S.,Rodriguez, O.L.,Himansu, S.,Zhou, J.,Hurtado, J.,Flynn, C.T.,McKenney, K.,Havenar-Daughton, C.,Saha, S.,Shields, K.,Schulze, S.,Smith, M.L.,Liang, C.H.,Toy, L.,Pecetta, S.,Lin, Y.C.,Willis, J.R.,Sesterhenn, F.,Kulp, D.W.,Hu, X.,Cottrell, C.A.,Zhou, X.,Ruiz, J.,Wang, X.,Nair, U.,Kirsch, K.H.,Cheng, H.L.,Davis, J.,Kalyuzhniy, O.,Liguori, A.,Diedrich, J.K.,Ngo, J.T.,Lewis, V.,Phelps, N.,Tingle, R.D.,Spencer, S.,Georgeson, E.,Adachi, Y.,Kubitz, M.,Eskandarzadeh, S.,Elsliger, M.A.,Amara, R.R.,Landais, E.,Briney, B.,Burton, D.R.,Carnathan, D.G.,Silvestri, G.,Watson, C.T.,Yates 3rd, J.R.,Paulson, J.C.,Crispin, M.,Grigoryan, G.,Ward, A.B.,Sok, D.,Alt, F.W.,Wilson, I.A.,Batista, F.D.,Crotty, S.,Schief, W.R.
Vaccination induces broadly neutralizing antibody precursors to HIV gp41.
Nat.Immunol., 25:1073-1082, 2024

PubMed Abstract: A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.

PubMed: 38816615
DOI: 10.1038/s41590-024-01833-w

Experimental method

X-RAY DIFFRACTION (2.66 Å)