3VGX

Structure of gp41 T21/Cp621-652

Summary for 3VGX

• Entry DOI: 10.2210/pdb3vgx/pdb
• Related: 3VGY 3VH7
• Descriptor: Envelope glycoprotein gp160, ACETIC ACID, GLYCEROL, ... (5 entities in total)
• Functional Keywords: 6-helix bundle, membrane fusion, membrane protein
• Biological source: Human immunodeficiency virus type 1 (HIV-1); More
• Cellular location: Transmembrane protein gp41: Virion membrane; Single-pass type I membrane protein. Surface protein gp120: Virion membrane; Peripheral membrane protein: P03375 P03375
• Total number of polymer chains: 2
• Total formula weight: 8693.82

Authors

Yao, X.,Waltersperger, S.,Wang, M.,Cui, S. (deposition date: 2011-08-22, release date: 2012-04-25, Last modification date: 2024-11-06)

Primary citation

Chong, H.,Yao, X.,Qiu, Z.,Qin, B.,Han, R.,Waltersperger, S.,Wang, M.,Cui, S.,He, Y.
Discovery of critical residues for viral entry and inhibition through structural Insight of HIV-1 fusion inhibitor CP621-652.
J.Biol.Chem., 287:20281-20289, 2012

PubMed Abstract: The core structure of HIV-1 gp41 is a stable six-helix bundle (6-HB) folded by its trimeric N- and C-terminal heptad repeats (NHR and CHR). We previously identified that the (621)QIWNNMT(627) motif located at the upstream region of gp41 CHR plays critical roles for the stabilization of the 6-HB core and peptide CP621-652 containing this motif is a potent HIV-1 fusion inhibitor, however, the molecular determinants underlying the stability and anti-HIV activity remained elusive. In this study, we determined the high-resolution crystal structure of CP621-652 complexed by T21. We find that the (621)QIWNNMT(627) motif does not maintain the α-helical conformation. Instead, residues Met(626) and Thr(627) form a unique hook-like structure (denoted as M-T hook), in which Thr(627) redirects the peptide chain to position Met(626) above the left side of the hydrophobic pocket on the NHR trimer. The side chain of Met(626) caps the hydrophobic pocket, stabilizing the interaction between the pocket and the pocket-binding domain. Our mutagenesis studies demonstrate that mutations of the M-T hook residues could completely abolish HIV-1 Env-mediated cell fusion and virus entry, and significantly destabilize the interaction of NHR and CHR peptides and reduce the anti-HIV activity of CP621-652. Our results identify an unusual structural feature that stabilizes the six-helix bundle, providing novel insights into the mechanisms of HIV-1 fusion and inhibition.

PubMed: 22511760
DOI: 10.1074/jbc.M112.354126

Experimental method

X-RAY DIFFRACTION (1.74 Å)