4XMK

Crystal structure of Fab of HIV-1 gp120 V3-specific human monoclonal antibody 2424 in complex with JR-FL V3 peptide

Summary for 4XMK

• Entry DOI: 10.2210/pdb4xmk/pdb
• Related: 4XMK
• Descriptor: Light chain of HIV-1 gp120 V3-specific human monoclonal antibody 2424, Heavy chain of HIV-1 gp120 V3-specific human monoclonal antibody 2424, HIV-1 JR-FL gp120 V3 peptide (3 entities in total)
• Functional Keywords: hiv-1 gp120, monoclonal antibody, immune system-viral protein complex, immune system/viral protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 9
• Total formula weight: 145389.11

Authors

Kong, X.-P.,Pan, R. (deposition date: 2015-01-14, release date: 2015-07-08, Last modification date: 2024-10-16)

Primary citation

Kumar, R.,Pan, R.,Upadhyay, C.,Mayr, L.,Cohen, S.,Wang, X.H.,Balasubramanian, P.,Nadas, A.,Seaman, M.S.,Zolla-Pazner, S.,Gorny, M.K.,Kong, X.P.,Hioe, C.E.
Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 with Neutralizing Activity against HIV-1 JRFL.
J.Virol., 89:9090-9102, 2015

PubMed Abstract: The V3 region of HIV-1 gp120 is important for virus-coreceptor interaction and highly immunogenic. Although most anti-V3 antibodies neutralize only the sensitive tier 1 viruses, anti-V3 antibodies effective against the more resistant viruses exist, and a better understanding of these antibodies and their epitopes would be beneficial for the development of novel vaccine immunogens against HIV. The HIV-1 isolate JRFL with its cryptic V3 is resistant to most V3-specific monoclonal antibodies (MAbs). However, the V3 MAb 2424 achieves 100% neutralization against JRFL. 2424 is encoded by IGHV3-53 and IGLV2-28 genes, a pairing rarely used by the other V3 MAbs. 2424 also has distinct binding and neutralization profiles. Studies of 2424-mediated neutralization of JRFL produced with a mannosidase inhibitor further revealed that its neutralizing activity is unaffected by the glycan composition of the virus envelope. To understand the distinct activity of 2424, we determined the crystal structure of 2424 Fab in complex with a JRFL V3 peptide and showed that the 2424 epitope is located at the tip of the V3 crown ((307)IHIGPGRAFYT(319)), dominated by interactions with His(P308), Pro(P313), and Arg(P315). The binding mode of 2424 is similar to that of the well-characterized MAb 447-52D, although 2424 is more side chain dependent. The 2424 epitope is focused on the very apex of V3, away from nearby glycans, facilitating antibody access. This feature distinguishes the 2424 epitope from the other V3 crown epitopes and indicates that the tip of V3 is a potential site to target and incorporate into HIV vaccine immunogens.

PubMed: 26109728
DOI: 10.1128/JVI.01280-15

Experimental method

X-RAY DIFFRACTION (3.179 Å)