3IDJ: Crystal structure of the HIV-1 Cross Neutralizing Monoclonal Antibody 2F5 Fab' fragment in complex with gp41 Peptide analog ELD(Orn)WAS

The quest to create a human immunodeficiency virus type 1 (HIV-1) vaccine capable of eliciting broadly neutralizing antibodies against Env has been challenging. Among other problems, one difficulty in creating a potent immunogen resides in the substantial overall sequence variability of the HIV envelope protein. The membrane-proximal region (MPER) of gp41 is a particularly conserved tryptophan-rich region spanning residues 659 to 683, which is recognized by three broadly neutralizing monoclonal antibodies (bnMAbs), 2F5, Z13, and 4E10. In this study, we first describe the variability of residues in the gp41 MPER and report on the invariant nature of 15 out of 25 amino acids comprising this region. Subsequently, we evaluate the ability of the bnMAb 2F5 to recognize 31 varying sequences of the gp41 MPER at a molecular level. In 19 cases, resulting crystal structures show the various MPER peptides bound to the 2F5 Fab'. A variety of amino acid substitutions outside the 664DKW666 core epitope are tolerated. However, changes at the 664DKW666 motif itself are restricted to those residues that preserve the aspartate's negative charge, the hydrophobic alkyl-pi stacking arrangement between the beta-turn lysine and tryptophan, and the positive charge of the former. We also characterize a possible molecular mechanism of 2F5 escape by sequence variability at position 667, which is often observed in HIV-1 clade C isolates. Based on our results, we propose a somewhat more flexible molecular model of epitope recognition by bnMAb 2F5, which could guide future attempts at designing small-molecule MPER-like vaccines capable of eliciting 2F5-like antibodies.
PDB ID: 3IDJDownload
MMDB ID: 79743
PDB Deposition Date: 2009/7/21
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.24  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 3IDJ: trimeric; determined by author and by software (PISA)
Molecular Components in 3IDJ
Label Count Molecule
Proteins (3 molecules)
2F5 FAB Light Chain
Molecule annotation
2F5 FAB Heavy Chain
Molecule annotation
Gp41 Mper Peptide Analog
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB