4M62: Ontogeny Of Recognition Specificity And Functionality For The Anti-hiv Neutralizing Antibody 4e10

Citation:
Abstract
The process of antibody ontogeny typically improves affinity, on-rate, and thermostability, narrows polyspecificity, and rigidifies the combining site to the conformer optimal for binding from the broader ensemble accessible to the precursor. However, many broadly-neutralizing anti-HIV antibodies incorporate unusual structural elements and recognition specificities or properties that often lead to autoreactivity. The ontogeny of 4E10, an autoreactive antibody with unexpected combining site flexibility, was delineated through structural and biophysical comparisons of the mature antibody with multiple potential precursors. 4E10 gained affinity primarily by off-rate enhancement through a small number of mutations to a highly conserved recognition surface. Controverting the conventional paradigm, the combining site gained flexibility and autoreactivity during ontogeny, while losing thermostability, though polyspecificity was unaffected. Details of the recognition mechanism, including inferred global effects due to 4E10 binding, suggest that neutralization by 4E10 may involve mechanisms beyond simply binding, also requiring the ability of the antibody to induce conformational changes distant from its binding site. 4E10 is, therefore, unlikely to be re-elicited by conventional vaccination strategies.
PDB ID: 4M62Download
MMDB ID: 123583
PDB Deposition Date: 2013/8/8
Updated in MMDB: 2014/10
Experimental Method:
x-ray diffraction
Resolution: 1.8  Å
Source Organism:
Salmonella enterica
Similar Structures:
Biological Unit for 4M62: trimeric; determined by author and by software (PISA)
Molecular Components in 4M62
Label Count Molecule
Proteins (3 molecules)
1
Gep2 FV Light Chain
Molecule annotation
1
Gep2 FV Heavy Chain
Molecule annotation
1
T117
Molecule annotation
Chemicals (4 molecules)
1
4
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.