4I3R

Crystal structure of the outer domain of HIV-1 gp120 in complex with VRC-PG04 space group P3221

Summary for 4I3R

• Entry DOI: 10.2210/pdb4i3r/pdb
• Related: 3ngb 3se8 3se9 3tyg 4I3S
• Descriptor: Outer domain of HIV-1 gp120 (KER2018 OD4.2.2), Heavy chain of VRC-PG04 Fab, Light chain of VRC-PG04 Fab, ... (5 entities in total)
• Functional Keywords: antibody affinity, antibody specificity, binding sites, hiv infections, antibodies, hiv envelope protein gp120, aids vaccines, amino acid sequence, antigens, epitopes, hiv antibodies, cd4, somatic mutation, sequence engineering, complementarity determining regions, immunoglobulin fab fragments, sera, viral protein-immune system complex, viral protein/immune system
• Biological source: Human Immunodeficiency Virus; More
• Total number of polymer chains: 3
• Total formula weight: 69377.60

Authors

Joyce, M.G.,Biertumpfel, C.,Nabel, G.J.,Kwong, P.D. (deposition date: 2012-11-26, release date: 2013-01-09, Last modification date: 2023-09-20)

Primary citation

Joyce, M.G.,Kanekiyo, M.,Xu, L.,Biertumpfel, C.,Boyington, J.C.,Moquin, S.,Shi, W.,Wu, X.,Yang, Y.,Yang, Z.Y.,Zhang, B.,Zheng, A.,Zhou, T.,Zhu, J.,Mascola, J.R.,Kwong, P.D.,Nabel, G.J.
Outer Domain of HIV-1 gp120: Antigenic Optimization, Structural Malleability, and Crystal Structure with Antibody VRC-PG04.
J.Virol., 87:2294-2306, 2013

PubMed Abstract: The outer domain of the HIV-1 gp120 envelope glycoprotein contains the epitope for broadly neutralizing antibodies directed to the CD4-binding site, many of which are able to neutralize over 90% of circulating HIV-1 isolates. While the outer domain is conformationally more stable than other portions of the HIV-1 envelope, efforts to express the outer domain as an immunogen for eliciting broadly neutralizing antibodies have not been successful, potentially because natural outer domain variants do not bind strongly to antibodies such as VRC01. In this study, we optimized the antigenic properties of the HIV-1 Env outer domain to generate OD4.2.2, from the KER2018 strain of clade A HIV-1, enabling it to bind antibodies such as VRC01 with nanomolar affinity. The crystal structure of OD4.2.2 in complex with VRC-PG04 was solved at 3.0-Å resolution and compared to known crystal structures including (i) the structure of core gp120 bound by VRC-PG04 and (ii) a circularly permutated version of the outer domain in complex with antibody PGT128. Much of the VRC-PG04 epitope was preserved in the OD4.2.2 structure, though with altered N and C termini conformations. Overall, roughly one-third of the outer domain structure appeared to be fixed in conformation, independent of alterations in termini, clade, or ligand, while other portions of the outer domain displayed substantial structural malleability. The crystal structure of OD4.2.2 with VRC-PG04 provides atomic-level details for an HIV-1 domain recognized by broadly neutralizing antibodies and insights relevant to the rational design of an immunogen that could elicit such antibodies by vaccination.

PubMed: 23236069
DOI: 10.1128/JVI.02717-12

Experimental method

X-RAY DIFFRACTION (3 Å)