1DLB

HELICAL INTERACTIONS IN THE HIV-1 GP41 CORE REVEALS STRUCTURAL BASIS FOR THE INHIBITORY ACTIVITY OF GP41 PEPTIDES

1DLB の概要

• エントリーDOI: 10.2210/pdb1dlb/pdb
• 分子名称: HIV-1 ENVELOPE GLYCOPROTEIN GP41 (2 entities in total)
• 機能のキーワード: gp41, hiv-1, membrane fusion, hiv-1 inhibition, virus/viral protein, viral protein
• 由来する生物種: Human immunodeficiency virus 1; 詳細
• 細胞内の位置: Transmembrane protein gp41: Virion membrane; Single-pass type I membrane protein. Surface protein gp120: Virion membrane; Peripheral membrane protein: P04578
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 7864.78

構造登録者

Shu, W.,Liu, J.,Ji, H.,Rading, L.,Jiang, S.,Lu, M. (登録日: 1999-12-09, 公開日: 1999-12-15, 最終更新日: 2024-02-07)

主引用文献

Shu, W.,Liu, J.,Ji, H.,Radigen, L.,Jiang, S.,Lu, M.
Helical interactions in the HIV-1 gp41 core reveal structural basis for the inhibitory activity of gp41 peptides.
Biochemistry, 39:1634-1642, 2000

PubMed Abstract: The HIV-1 gp41 envelope protein mediates membrane fusion that leads to virus entry into the cell. The core structure of fusion-active gp41 is a six-helix bundle in which an N-terminal three-stranded coiled coil is surrounded by a sheath of antiparallel C-terminal helices. A conserved glutamine (Gln 652) buried in this helical interface replaced by leucine increases HIV-1 infectivity. To define the basis for this enhanced membrane fusion activity, we investigate the role of the Gln 652 to Leu substitution on the conformation, stability, and biological activity of the N34(L6)C28 model of the gp41 ectodomain core. The 2.0 A resolution crystal structure of the mutant molecule shows that the Leu 652 side chains make prominent contacts with hydrophobic grooves on the surface of the central coiled coil. The Gln 652 to Leu mutation leads to a marginal stabilization of the six-helix bundle by -0.8 kcal/mol, evaluated from thermal unfolding experiments. Strikingly, the mutant N34(L6)C28 peptide is a potent inhibitor of HIV-1 infection, with 10-fold greater activity than the wild-type molecule. This inhibitory potency can be traced to the corresponding C-terminal mutant peptide that likely has greater potential to interact with the coiled-coil trimer. These results provide strong evidence that conserved interhelical packing interactions in the gp41 core are important determinants of HIV-1 entry and its inhibition. These interactions also offer a test-bed for the development of more potent analogues of gp41 peptide inhibitors.

PubMed: 10677212
DOI: 10.1021/bi9921687

実験手法

X-RAY DIFFRACTION (2 Å)