A template-assembled model of the N-peptide helix bundle from HIV-1 Gp-41 with high affinity for C-peptide.
The infection of target cells by HIV-1 is initiated by fusion of the viral and cell membranes, which is mediated by the viral glycoproteins, gp120 and gp41. After initial cell binding by gp120, the folding of gp41 to form a stable six-helix bundle structure is directly associated with membrane fusion. This helix bundle is composed of an alpha-helical trimer of gp41 N-peptide, with three copies of the alpha-helical gp41 C-peptide folded onto it in an antiparallel orientation. This report describes the synthesis and study of an N-peptide three-helix bundle structure, KTA-3N29b, that is assembled on a threefold symmetric template derived from Kemp's triacid. At neutral pH and in the presence of physiologic salt, KTA-3N29b, exists as a monomer with high helix content. Binding isotherms measured by circular dichroism spectropolarimetry indicate that KTA-3N29b binds three copies of the C-peptide native sequence, with a KD of about 260 nM. These features of KTA-3N29b demonstrate that this templated three-helix bundle serves as a functional model for the native N-peptide structure that will allow detailed studies of the folding and thermodynamic stability of the gp41 six-helix bundle, and may aid the future development of potent HIV-1 fusion inhibitors and immunogens.
Xu
Weiming
W
Department of Chemistry and Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854, USA.
Taylor
John W
JW
D000595:Amino Acid Sequence; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002942:Circular Dichroism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D053586:Virus Internalization
D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; C514787:gp41 protein, Human immunodeficiency virus 1