Structure of the membrane proximal external region of HIV-1 envelope glycoprotein

Significance The conserved, membrane-proximal external region (MPER) of the HIV-1 envelope glycoprotein (Env) is a potential vaccine target. To visualize its structure in the context of a lipid-bilayer membrane, we have reconstituted a polypeptide containing the HIV-1 MPER and the contiguous transmembrane domain into a bilayer-like environment and determined its atomic structure by NMR. The MPER folds into a trimeric cluster, well exposed on the bilayer surface, even in the absence of the structural constraints from the rest of the Env ectodomain. Our analyses suggest that this structure probably represents a prefusion conformation of the MPER. The findings imply that presenting a well-defined structure will be important for MPER-based immunogen design. The membrane-proximal external region (MPER) of the HIV-1 envelope glycoprotein (Env) bears epitopes of broadly neutralizing antibodies (bnAbs) from infected individuals; it is thus a potential vaccine target. We report an NMR structure of the MPER and its adjacent transmembrane domain in bicelles that mimic a lipid-bilayer membrane. The MPER lies largely outside the lipid bilayer. It folds into a threefold cluster, stabilized mainly by conserved hydrophobic residues and potentially by interaction with phospholipid headgroups. Antigenic analysis and comparison with published images from electron cryotomography of HIV-1 Env on the virion surface suggest that the structure may represent a prefusion conformation of the MPER, distinct from the fusion-intermediate state targeted by several well-studied bnAbs. Very slow bnAb binding indicates that infrequent fluctuations of the MPER structure give these antibodies occasional access to alternative conformations of MPER epitopes. Mutations in the MPER not only impede membrane fusion but also influence presentation of bnAb epitopes in other regions. These results suggest strategies for developing MPER-based vaccine candidates.