4LAJ

Crystal structure of HIV-1 YU2 envelope gp120 glycoprotein in complex with CD4-mimetic miniprotein, M48U1, and llama single-domain, broadly neutralizing, co-receptor binding site antibody, JM4

4LAJ の概要

• エントリーDOI: 10.2210/pdb4laj/pdb
• 関連するPDBエントリー: 4JZW 4JZZ
• 関連するBIRD辞書のPRD_ID: PRD_001094
• 分子名称: HIV-1 YU2 gp120 envelope glycoprotein, CD4-mimetic miniprotein M48U1, Llama single domain antibody, JM4, ... (7 entities in total)
• 機能のキーワード: cd4-induced antibody, hiv-1 neutralizing antibody, hiv-1 gp120 reactive, viral protein-inhibitor complex, viral protein/inhibitor
• 由来する生物種: Human immunodeficiency virus 1 (HIV-1); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 243358.81

構造登録者

Acharya, P.,Luongo, T.S.,Kwong, P.D. (登録日: 2013-06-20, 公開日: 2013-08-14, 最終更新日: 2023-11-15)

主引用文献

Acharya, P.,Luongo, T.S.,Georgiev, I.S.,Matz, J.,Schmidt, S.D.,Louder, M.K.,Kessler, P.,Yang, Y.,McKee, K.,O'Dell, S.,Chen, L.,Baty, D.,Chames, P.,Martin, L.,Mascola, J.R.,Kwong, P.D.
Heavy Chain-Only IgG2b Llama Antibody Effects Near-Pan HIV-1 Neutralization by Recognizing a CD4-Induced Epitope That Includes Elements of Coreceptor- and CD4-Binding Sites.
J.Virol., 87:10173-10181, 2013

PubMed Abstract: The conserved HIV-1 site of coreceptor binding is protected from antibody-directed neutralization by conformational and steric restrictions. While inaccessible to most human antibodies, the coreceptor site has been shown to be accessed by antibody fragments. In this study, we used X-ray crystallography, surface plasmon resonance, and pseudovirus neutralization to characterize the gp120-envelope glycoprotein recognition and HIV-1 neutralization of a heavy chain-only llama antibody, named JM4. We describe full-length IgG2b and IgG3 versions of JM4 that target the coreceptor-binding site and potently neutralize over 95% of circulating HIV-1 isolates. Contrary to established trends that show improved access to the coreceptor-binding region by smaller antibody fragments, the single-domain (VHH) version of JM4 neutralized less well than the full-length IgG2b version of JM4. The crystal structure at 2.1-Å resolution of VHH JM4 bound to HIV-1 YU2 gp120 stabilized in the CD4-bound state by the CD4-mimetic miniprotein, M48U1, revealed a JM4 epitope that combined regions of coreceptor recognition (including the gp120 bridging sheet, V3 loop, and β19 strand) with gp120 structural elements involved in recognition of CD4 such as the CD4-binding loop. The structure of JM4 with gp120 thus defines a novel CD4-induced site of vulnerability involving elements of both coreceptor- and CD4-binding sites. The potently neutralizing JM4 IgG2b antibody that targets this newly defined site of vulnerability adds to the expanding repertoire of broadly neutralizing antibodies that effectively neutralize HIV-1 and thereby potentially provides a new template for vaccine development and target for HIV-1 therapy.

PubMed: 23843638
DOI: 10.1128/JVI.01332-13

実験手法

X-RAY DIFFRACTION (2.14 Å)