Identification and characterization of a subpocket on the N-trimer of HIV-1 Gp41. (1st June 2015)

• Record Type: Journal Article
• Authors: Qiu, Zonglin; Chong, Huihui; Yao, Xue; Su, Yang; Cui, Sheng; He, Yuxian
• Is Part Of: AIDS. Volume 29:Number 9(2015)
• Publication Date: 2015-06-01
• Subjects: AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome; AIDS (Disease); Periodicals; Periodicals; 616.9792005
• DOI: 10.1097/QAD.0000000000000683
• Languages: English
• ISSNs: 0269-9370

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Objective:</title> <p>Crystallographic studies of HIV-1 gp41 demonstrate a stable six-helix bundle (6-HB) folded by trimeric N and C-terminal heptad repeats (NHR and CHR), and a deep hydrophobic pocket (pocket-1) on the NHR helices (N-trimer); however, previous crystal structures of 6-HB core were determined by peptide fragments missing the downstream sequence of pocket-1; thus, the structural features of this site could not be observed.</p> </sec> <sec> <title>Design:</title> <p>We recently determined several 6-HB structures containing the pocket-1 and its downstream site. Here, we focused to investigate the structural features of N-trimer previously uncharacterized.</p> </sec> <sec> <title>Methods:</title> <p>Biophysical, biochemical and functional approaches were combined to characterize the downstream residues of pocket-1.</p> </sec> <sec> <title>Results:</title> <p>A subpocket (designated pocket-2) was visualized on the C-terminal portion of N-trimer, which is formed by a cluster of seven residues, including Leu587, Lys588 and Glu584 on one NHR helix and Tyr586, Val583, Ala582 and Arg579 of another NHR helix. Mutagenesis studies demonstrated that the pocket-2 residues play essential roles for HIV-1 Env-mediated cell entry and critically determine the antiviral activity of NHR-derived peptide fusion inhibitor T21. Further, the pocket-2 mutations dramatically impaired the thermostability and conformation of 6-HB structure and reduced the binding affinity of CHR-derived inhibitor HP23 that specifically targets the deep pocket-1.</p> </sec> <sec> <title>Conclusion:</title> <p>These data have provided important information for the structure–function relationship of HIV-1 gp41 and for the development of antiviral entry inhibitors.</p> </sec> </abstract>