N and C terminal heptad repeat helices of gp41 form six-helix bundle

Stable Identifier
Reaction [transition]
Homo sapiens
Related Species
Human immunodeficiency virus 1
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The gp41 glycoprotein contains N- and C-terminal heptad repeats, which form a stable six-helical bundle. This six-helix bundle represents a fusion-active gp41 core, and its conformation is critical for membrane fusion. Among the interactions necessary for the six helix bundle conformation is the formation of a salt bridge between the Asp632 residue in the C-terminal heptad repeat and the Lys574 terminal in the N-terminal coiled-coil. Disruption of this interaction has been found to lead to destabilization of the six helix bundle formation, with a subsequent severe reduction in viral fusion activity. Also, the N-terminal heptad repeat alone was found to be important in viral fusion, as removal or truncation of this repeat reduced the fusion activity of the peptide even when the adjacent, full length N-terminal fusion peptide was in place. The bundle itself is formed during the fusion process, prior to pore formation but after insertion of the gp41 fusion peptide into the target cell membrane. Upon insertion of the fusion peptide, the three N-terminal helices of gp41 adjacent to the target cell membrane and three C-terminal helices adjacent to the viral membrane undergo a conformational change which brings them into close proximity with one another, creating a six-helix bundle and leading to eventual fusion.
Literature References
PubMed ID Title Journal Year
11591141 HIV-1 gp41 six-helix bundle formation occurs rapidly after the engagement of gp120 by CXCR4 in the HIV-1 Env-mediated fusion process

Gallo, SA, Blumenthal, R, Puri, A

Biochemistry 2001
7538176 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

Greenberg, ML, Bolognesi, DP, Matthews, TJ, Chen, CH, McDanal, CB

J Virol 1995
1629954 Mutations in the leucine zipper of the human immunodeficiency virus type 1 transmembrane glycoprotein affect fusion and infectivity

Dubay, JW, Hunter, E, Roberts, SJ, Brody, B

J Virol 1992
2364015 Retroviral envelope glycoproteins contain a leucine zipper-like repeat

Delwart, EL, Gilmore, T, Mosialos, G

AIDS Res Hum Retroviruses 1990
  Formation of a Salt Bridge between the N- and C-terminal Heptad Repeats of HIV-1 gp41 Is Critical for Stabilization of 6-Helix Bundle and Virus Fusion

Liu, S, Jiang, S, Debnath, AK, He, Y

9108481 Core structure of gp41 from the HIV envelope glycoprotein

Berger, JM, Kim, PS, Chan, DC, Fass, D

Cell 1997
8612573 The ectodomain of HIV-1 env subunit gp41 forms a soluble, alpha-helical, rod-like oligomer in the absence of gp120 and the N-terminal fusion peptide

Calder, LJ, Moss, B, Earl, PL, Weissenhorn, W, Skehel, JJ, Aliprandis, E, Wharton, SA, Wiley, DC

EMBO J 1996
9546217 Capture of an early fusion-active conformation of HIV-1 gp41

Furuta, RA, Weng, Y, Wild, CT, Weiss, CD

Nat Struct Biol 1998
11926830 The HIV-1 gp41 N-terminal heptad repeat plays an essential role in membrane fusion

Sackett, K, Shai, Y

Biochemistry 2002
2788443 A general model for the transmembrane proteins of HIV and other retroviruses

Griffin, MC, Ball, JM, Garry, RF, Montelaro, RC, Gallaher, WR

AIDS Res Hum Retroviruses 1989
15504864 N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion

Liu, S, Debnath, AK, Jiang, S, He, Y, Zhao, Q, Lu, H

Antimicrob Agents Chemother 2004
Name Identifier Synonyms
Human immunodeficiency virus infectious disease DOID:526 HIV infection
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