1dlb: Difference between revisions
New page: left|200px<br /> <applet load="1dlb" size="450" color="white" frame="true" align="right" spinBox="true" caption="1dlb, resolution 2.00Å" /> '''HELICAL INTERACTION... |
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[[Image:1dlb.gif|left|200px]]<br /> | [[Image:1dlb.gif|left|200px]]<br /><applet load="1dlb" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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'''HELICAL INTERACTIONS IN THE HIV-1 GP41 CORE REVEALS STRUCTURAL BASIS FOR THE INHIBITORY ACTIVITY OF GP41 PEPTIDES'''<br /> | '''HELICAL INTERACTIONS IN THE HIV-1 GP41 CORE REVEALS STRUCTURAL BASIS FOR THE INHIBITORY ACTIVITY OF GP41 PEPTIDES'''<br /> | ||
==Overview== | ==Overview== | ||
The HIV-1 gp41 envelope protein mediates membrane fusion that leads to | 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. | ||
==About this Structure== | ==About this Structure== | ||
1DLB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http:// | 1DLB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DLB OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: virus/viral protein]] | [[Category: virus/viral protein]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:17:46 2008'' | ||
Revision as of 13:17, 21 February 2008
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HELICAL INTERACTIONS IN THE HIV-1 GP41 CORE REVEALS STRUCTURAL BASIS FOR THE INHIBITORY ACTIVITY OF GP41 PEPTIDES
OverviewOverview
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.
About this StructureAbout this Structure
1DLB is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
ReferenceReference
Helical interactions in the HIV-1 gp41 core reveal structural basis for the inhibitory activity of gp41 peptides., Shu W, Liu J, Ji H, Radigen L, Jiang S, Lu M, Biochemistry. 2000 Feb 22;39(7):1634-42. PMID:10677212
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