2XRA

crystal structure of the HK20 Fab in complex with a gp41 mimetic 5- Helix

Summary for 2XRA

• Entry DOI: 10.2210/pdb2xra/pdb
• Related: 1AIK 1DF4 1DF5 1DLB 1G9M 1GC1 1GZL 1K33 1K34 1MZI 1OPN 1OPT 1OPW 1RZJ 2CMR
• Descriptor: TRANSMEMBRANE PROTEIN GP41, HK20, HUMAN MONOCLONAL ANTIBODY HEAVY CHAIN, HK20, HUMAN MONOCLONAL ANTIBODY LIGHT CHAIN, ... (4 entities in total)
• Functional Keywords: immune system, antibody, monoclonal cells, neutralization tests
• Biological source: SYNTHETIC CONSTRUCT; More
• Cellular location: Surface protein gp120: Virion membrane ; Peripheral membrane protein . Transmembrane protein gp41: Virion membrane ; Single-pass type I membrane protein : P04578
• Total number of polymer chains: 3
• Total formula weight: 72961.45

Authors

Sabin, C.,Corti, D.,Buzon, V.,Seaman, M.S.,Lutje Hulsik, D.,Hinz, A.,Vanzetta, F.,Agatic, G.,Silacci, C.,Langedijk, J.P.M.,Mainetti, L.,Scarlatti, G.,Sallusto, F.,Weiss, R.,Lanzavecchia, A.,Weissenhorn, W. (deposition date: 2010-09-13, release date: 2010-12-15, Last modification date: 2024-10-23)

Primary citation

Sabin, C.,Corti, D.,Buzon, V.,Seaman, M.S.,Lutje Hulsik, D.,Hinz, A.,Vanzetta, F.,Agatic, G.,Silacci, C.,Mainetti, L.,Scarlatti, G.,Sallusto, F.,Weiss, R.,Lanzavecchia, A.,Weissenhorn, W.
Crystal structure and size-dependent neutralization properties of HK20, a human monoclonal antibody binding to the highly conserved heptad repeat 1 of gp41.
PLoS Pathog., 6:e1001195-e1001195, 2010

PubMed Abstract: The human monoclonal antibody (mAb) HK20 neutralizes a broad spectrum of primary HIV-1 isolates by targeting the highly conserved heptad repeat 1 (HR1) of gp41, which is transiently exposed during HIV-1 entry. Here we present the crystal structure of the HK20 Fab in complex with a gp41 mimetic 5-Helix at 2.3 Å resolution. HK20 employs its heavy chain CDR H2 and H3 loops to bind into a conserved hydrophobic HR1 pocket that is occupied by HR2 residues in the gp41 post fusion conformation. Compared to the previously described HR1-specific mAb D5, HK20 approaches its epitope with a different angle which might favor epitope access and thus contribute to its higher neutralization breadth and potency. Comparison of the neutralization activities of HK20 IgG, Fab and scFv employing both single cycle and multiple cycle neutralization assays revealed much higher potencies for the smaller Fab and scFv over IgG, implying that the target site is difficult to access for complete antibodies. Nevertheless, two thirds of sera from HIV-1 infected individuals contain significant titers of HK20-inhibiting antibodies. The breadth of neutralization of primary isolates across all clades, the higher potencies for C-clade viruses and the targeting of a distinct site as compared to the fusion inhibitor T-20 demonstrate the potential of HK20 scFv as a therapeutic tool.

PubMed: 21124990
DOI: 10.1371/journal.ppat.1001195

Experimental method

X-RAY DIFFRACTION (2.3 Å)