HIV-1 Envelope Protein gp41: An NMR Study of Dodecyl Phosphocholine Embedded gp41 Reveals a Dynamic Prefusion Intermediate Conformation

Human immunodeficiency viral (HIV-1) fusion is mediated by the viral envelope gp120/gp41 complex (ENVelope glycoprotein). After gp120 shedding, gp41 is exposed and elicits membrane fusion via a cascade of conformational changes. In contrast to prefusion and postfusion conformation, little is known about any intermediate conformation. We report on a solution NMR investigation of homotrimeric HIV-1 gp4127–194, comprising the transmembrane region and reconstituted in dodecyl phosphocholine (DPC) micelles. The protein is mainly α-helical, but experiences internal dynamics on the nanosecond and micro to millisecond time scale and transient α-helical behavior for certain residues in the N-terminal heptad repeat (NHR). Strong lipid interactions are observed, in particular for C-terminal residues of the NHR and imunodominant loop region connecting NHR and C-terminal heptad repeat (CHR). Our data indicate an extended conformation with features anticipated for a prefusion intermediate, presumably in exchange with a lowly populated postfusion six-helical bundle conformation. [Display omitted] •HIV-1 gp41 shows high internal dynamics on different time scales (low ns and μs-ms).•Extended (dynamic) helical conformation as expected for a prefusion intermediate•Strong lipid interactions of immunodominant loop region and C-terminal NHR•Transient α-helical notches in NHR allow breaking points for conformational changes Lakomek et al. use NMR to study HIV-1 gp41 under conditions that elicit viral fusion and reveal high internal flexibility and conformational dynamics of gp41 as well as strong lipid interactions of non-TM regions. The data are compatible with an extended helical conformation of a prefusion intermediate.