1DLB
HELICAL INTERACTIONS IN THE HIV-1 GP41 CORE REVEALS STRUCTURAL BASIS FOR THE INHIBITORY ACTIVITY OF GP41 PEPTIDES
Summary for 1DLB
| Entry DOI | 10.2210/pdb1dlb/pdb |
| Descriptor | HIV-1 ENVELOPE GLYCOPROTEIN GP41 (2 entities in total) |
| Functional Keywords | gp41, hiv-1, membrane fusion, hiv-1 inhibition, virus/viral protein, viral protein |
| Biological source | Human immunodeficiency virus 1 More |
| Cellular location | Transmembrane protein gp41: Virion membrane; Single-pass type I membrane protein. Surface protein gp120: Virion membrane; Peripheral membrane protein: P04578 |
| Total number of polymer chains | 1 |
| Total formula weight | 7864.78 |
| Authors | |
| Primary citation | 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 Cited by 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: 10677212DOI: 10.1021/bi9921687 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
Download full validation report
