5IQ7

Crystal structure of 10E8-S74W Fab in complex with an HIV-1 gp41 peptide.

5IQ7 の概要

• エントリーDOI: 10.2210/pdb5iq7/pdb
• 分子名称: 10E8-S74W Heavy Chain, 10E8-S74W Light Chain, gp41 MPER peptide (3 entities in total)
• 機能のキーワード: immunoglobulin, mper, antibody, immune system
• 由来する生物種: Homo sapiens; 詳細
• 細胞内の位置: Secreted : P01857
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 52511.61

構造登録者

Ofek, G.,Kwon, Y.D.,Caruso, W.,Kwong, P.D. (登録日: 2016-03-10, 公開日: 2016-04-20, 最終更新日: 2024-11-06)

主引用文献

Kwon, Y.D.,Georgiev, I.S.,Ofek, G.,Zhang, B.,Asokan, M.,Bailer, R.T.,Bao, A.,Caruso, W.,Chen, X.,Choe, M.,Druz, A.,Ko, S.Y.,Louder, M.K.,McKee, K.,O'Dell, S.,Pegu, A.,Rudicell, R.S.,Shi, W.,Wang, K.,Yang, Y.,Alger, M.,Bender, M.F.,Carlton, K.,Cooper, J.W.,Blinn, J.,Eudailey, J.,Lloyd, K.,Parks, R.,Alam, S.M.,Haynes, B.F.,Padte, N.N.,Yu, J.,Ho, D.D.,Huang, J.,Connors, M.,Schwartz, R.M.,Mascola, J.R.,Kwong, P.D.
Optimization of the Solubility of HIV-1-Neutralizing Antibody 10E8 through Somatic Variation and Structure-Based Design.
J.Virol., 90:5899-5914, 2016

PubMed Abstract: Extraordinary antibodies capable of near pan-neutralization of HIV-1 have been identified. One of the broadest is antibody 10E8, which recognizes the membrane-proximal external region (MPER) of the HIV-1 envelope and neutralizes >95% of circulating HIV-1 strains. If delivered passively, 10E8 might serve to prevent or treat HIV-1 infection. Antibody 10E8, however, is markedly less soluble than other antibodies. Here, we describe the use of both structural biology and somatic variation to develop optimized versions of 10E8 with increased solubility. From the structure of 10E8, we identified a prominent hydrophobic patch; reversion of four hydrophobic residues in this patch to their hydrophilic germ line counterparts resulted in an ∼10-fold decrease in turbidity. We also used somatic variants of 10E8, identified previously by next-generation sequencing, to optimize heavy and light chains; this process yielded several improved variants. Of these, variant 10E8v4 with 26 changes versus the parent 10E8 was the most soluble, with a paratope we showed crystallographically to be virtually identical to that of 10E8, a potency on a panel of 200 HIV-1 isolates also similar to that of 10E8, and a half-life in rhesus macaques of ∼10 days. An anomaly in 10E8v4 size exclusion chromatography that appeared to be related to conformational isomerization was resolved by engineering an interchain disulfide. Thus, by combining a structure-based approach with natural variation in potency and solubility from the 10E8 lineage, we successfully created variants of 10E8 which retained the potency and extraordinary neutralization breadth of the parent 10E8 but with substantially increased solubility.

PubMed: 27053554
DOI: 10.1128/JVI.03246-15

実験手法

X-RAY DIFFRACTION (3.2869 Å)