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. 2022 Oct 27;13:6393. doi: 10.1038/s41467-022-34008-y

Fig. 6. Model for stepwise binding of an anti-MPER bnAb to the HIV-1 Env protein.

Fig. 6

The gp145 ectodomain is shown in gray, CHR in orange, MPER-N in green, MPER-C in magenta, and the transmembrane domain in light blue. The lipid bilayer is shown in pale yellow/brown and the antibody in bright yellow. a In the upright orientation of the Env protein, the MPER epitope for bnAb 4E10 (indicated by *) is occluded by the ectodomain, making it inaccessible to the bnAb, and is most of the time not exposed but buried in the membrane. Tilting of the ectodomain transiently makes the opposing MPER accessible and if this coincides with at least partial exposure of the epitope, the bnAb can make first interactions. Full antibody binding both alters MPER motion on the membrane and creates strain on the transmembrane domains, thus preventing further conformational changes required for membrane fusion. b Structural alignment of Fabs of MPER-targeting bnAbs bound to HIV-1 Env. The Fabs of bnAbs 4E10 (PDB: 4XC3), DH511 (PDB: 5U3N), 10E8 (PDB: 4U6G), and PGZL1 (PDB: 6O3J) were aligned based on the consensus MPER epitope (magenta), showing that all MPER-C targeting bnAbs bind to HIV-1 Env in a similar fashion. Note that the lipid-interaction surface of 4E10 is more hydrophobic than that of the other bnAbs26.