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

Citation:
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-A 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 beta19 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.
PDB ID: 4LAJDownload
MMDB ID: 112661
PDB Deposition Date: 2013/6/20
Updated in MMDB: 2013/09
Experimental Method:
x-ray diffraction
Resolution: 2.14  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 4LAJ: trimeric; determined by author and by software (PISA)
Molecular Components in 4LAJ
Label Count Molecule
Proteins (3 molecules)
1
Hiv-1 YU2 Gp120 Envelope Glycoprotein
Molecule annotation
1
Cd4-mimetic Miniprotein M48u1
Molecule annotation
1
Llama Single Domain Antibody, JM4
Molecule annotation
Chemicals (12 molecules)
1
11
2
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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