Human Fab PG16

Crystal structure of human Fab PG16, a broadly reactive and potent HIV-1 neutralizing antibody (3mug)

About this Structure

3mug is a 12 chains structure with sequences from Homo sapiens. Full crystallographic information is available from OCA.

HIV-1 vaccination has remained an elusive goal primarily due to the difficulty in finding broadly neutralizing antibodies (bNAb) responses targeting the envelope glycoproteins of HIV-1, gp120 and gp41. PG9 and PG16 are exciting new monoclonal antibodies (mAbs) which have shown approximately an order of magnitude higher potency against HIV-1 viral particles than previously described mAbs.

Upon investigation of the antigen binding fragment (Fab) of PG16, researchers discovered that the monoclinic crystals of PG16 Fab contain six Fab molecules in the asymmetric unit with three chemically distinct environments ^[1]. The unusually long, 28-residue CDR H3 has a canonical, β-bulge torso conformation which forms a unique, hammerhead structure that towers above the antibody surface ^[2]. It is believed that this unique hammerhead structure might play a significant role in HIV-1 trimeric surface envelope glycoprotein (Env) binding and neutralization ^[1]. Another unusual attribute is that CDR H3 protrudes from the antibody and folds as a semi-independent sub-domain. In the few observed structural homologs, the "hammerhead" or "axe" motif is used as a structural building block and is an integral part of other domains ^[3].

It is postulated that the very long CDR H3 loops can form subdomains which impart much of the specificity and affinity of the antibody. After exchange of small residue stretches in loop 1 of H3 between PG9 and PG16 it was observed that the PG16 swap variant mimicked the neutralization profile of PG9. In addition to the unusual CDR H3 subdomain, researchers have found that PG16 and PG9 both demonstrate unusual N-linked glycosylation and extensive affinity maturation ^[3] Structural studies have suggested that it is these two attributes, extensive affinity maturation and the CRD H3 loops, which are the most important elements involved in PG16 and PG9 potency against HIV ^[3].

See Antibody for additional structural information.