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Structural insight of HIV-1 fusion inhibitor CP621-652 discovers the critical residues for viral entry and inhibition.
The Journal of biological chemistry 2012 Apr 16; In press
Chong H, Yao X, Qiu Z, Qin B, Han R, Waltersperger S, Wang M, Cui S, He Y
Chinese Academy of Medical Sciences, China;
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 621QIWNNMT627 motif located at the upstream region of the gp41 CHR plays critical roles for the stabilization of the 6-HB core and the 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 high-resolution crystal structure of CP621-652 complexed by T21. We find that the 621QIWNNMT627 motif does not maintain the α-helical comformation. Instead, residues Met626 and Thr627 form a unique hook-like structure (denoted as M-T hook), in which Thr627 redirects the peptide chain to position Met626 above the left side of hydrophobic pocket on the NHR trimer. The side chain of Met626 caps the hydrophobic pocket, stabilizing the interaction between the pocket and the pocket binding domain (PBD). 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 the novel insights into HIV-1 fusion mechanism and fusion inhibitor designing.