5JNY
Crystal Structure of 10E8 Fab
Summary for 5JNY
| Entry DOI | 10.2210/pdb5jny/pdb |
| Descriptor | 10E8 Heavy Chain, 10E8 Light Chain, ISOPROPYL ALCOHOL, ... (5 entities in total) |
| Functional Keywords | mper, hiv, antibody, neutralizing, immune system |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 4 |
| Total formula weight | 96596.99 |
| Authors | |
| Primary citation | Soto, C.,Ofek, G.,Joyce, M.G.,Zhang, B.,McKee, K.,Longo, N.S.,Yang, Y.,Huang, J.,Parks, R.,Eudailey, J.,Lloyd, K.E.,Alam, S.M.,Haynes, B.F.,Mullikin, J.C.,Connors, M.,Mascola, J.R.,Shapiro, L.,Kwong, P.D. Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8. Plos One, 11:e0157409-e0157409, 2016 Cited by PubMed Abstract: Antibody 10E8 targets the membrane-proximal external region (MPER) of HIV-1 gp41, neutralizes >97% of HIV-1 isolates, and lacks the auto-reactivity often associated with MPER-directed antibodies. The developmental pathway of 10E8 might therefore serve as a promising template for vaccine design, but samples from time-of-infection-often used to infer the B cell record-are unavailable. In this study, we used crystallography, next-generation sequencing (NGS), and functional assessments to infer the 10E8 developmental pathway from a single time point. Mutational analysis indicated somatic hypermutation of the 2nd-heavy chain-complementarity determining region (CDR H2) to be critical for neutralization, and structures of 10E8 variants with V-gene regions reverted to genomic origin for heavy-and-light chains or heavy chain-only showed structural differences >2 Å relative to mature 10E8 in the CDR H2 and H3. To understand these developmental changes, we used bioinformatic sieving, maximum likelihood, and parsimony analyses of immunoglobulin transcripts to identify 10E8-lineage members, to infer the 10E8-unmutated common ancestor (UCA), and to calculate 10E8-developmental intermediates. We were assisted in this analysis by the preservation of a critical D-gene segment, which was unmutated in most 10E8-lineage sequences. UCA and early intermediates weakly bound a 26-residue-MPER peptide, whereas HIV-1 neutralization and epitope recognition in liposomes were only observed with late intermediates. Antibody 10E8 thus develops from a UCA with weak MPER affinity and substantial differences in CDR H2 and H3 from the mature 10E8; only after extensive somatic hypermutation do 10E8-lineage members gain recognition in the context of membrane and HIV-1 neutralization. PubMed: 27299673DOI: 10.1371/journal.pone.0157409 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.041 Å) |
Structure validation
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