A molecular clasp in the human immunodeficiency virus (HIV) type 1 TM protein determines the anti-HIV activity of gp41 derivatives: implication for viral fusion.
We have previously reported that synthetic peptides representing the leucine zipper domain (DP107) and a second putative helical domain (DP178) of human immunodeficiency virus type 1 (HIV-1) gp41 exhibit potent anti-HIV activity. In this study we have used soluble recombinant forms of gp41 to provide evidence that the DP178 peptide and the DP178 region of gp41 associate with a distal site on the gp41 transmembrane protein whose interactive structure is influenced by the leucine zipper (DP107) motif. We also observed that a single coiled-coil-disrupting mutation in the leucine zipper domain transformed the recombinant gp41 protein from an inactive to an active inhibitor of HIV-1 fusion and infectivity, which may be related to that finding. We speculate that this transformation results from liberation of the potent DP178-related sequence from a molecular clasp with a leucine zipper, DP107, determinant. The results are discussed in the context of two distinct conformations for the gp41 molecule and possible involvement of these two domains in structural transitions associated with HIV-1-mediated fusion. The results are also interpreted to suggest that the anti-HIV activity of the various gp41 derivatives (peptides and recombinant proteins) may be due to their ability to form complexes with viral gp41 and interfere with its fusogenic processes.
Chen
C H
CH
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Matthews
T J
TJ
McDanal
C B
CB
Bolognesi
D P
DP
Greenberg
M L
ML
D000998:Antiviral Agents / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D000939:Epitopes / Q000737:chemistry; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D016350:Leucine Zippers / Q000235:genetics; D008561:Membrane Fusion; D008969:Molecular Sequence Data; D009154:Mutation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D017931:DNA Primers; D000939:Epitopes; D015700:HIV Envelope Protein gp41; D011993:Recombinant Fusion Proteins