3cp1
From Proteopedia
(New page: '''Unreleased structure''' The entry 3cp1 is ON HOLD until Paper Publication Authors: Wang, Z.M., Dwyer, J.J. Description: Structure of a longer thermalstable core domain of HIV-1 gp41...) |
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| + | {{STRUCTURE_3cp1| PDB=3cp1 | SCENE= }} | ||
| - | + | '''Structure of a longer thermalstable core domain of HIV-1 gp41 containing the enfuvirtide resistance mutation N43D''' | |
| - | Description: Structure of a longer thermalstable core domain of HIV-1 gp41 containing the enfuvirtide resistance mutation N43D | ||
| + | ==Overview== | ||
| + | Enfuvirtide (ENF), the first human immunodeficiency virus type 1 (HIV-1) fusion inhibitor approved for clinical use, acts by binding to gp41 heptad repeat 1 (HR1) and preventing its interaction with the viral HR2 region. Treatment-emergent resistance to ENF has been mapped to residues within HR1, and these mutations decrease its susceptibility to ENF and may reduce viral fitness and pathogenesis, although the mechanism for these effects is not clear. N43D, a common ENF resistance mutation, was found in in vitro assays to cause a 5-50-fold in antiviral activity. We introduced this mutation into peptide models and determined the impact of this mutation by circular dichroism and X-ray crystallography. We find that the mutation results in a decrease in the thermal stability of the six-helix bundle and causes a significant change in the HR1-HR2 interface, including a loss of HR2 helicity. These data form a mechanistic basis for the decrease in ENF sensitivity and six-helix bundle stability. The E137K polymorphism, generally present at baseline in patients who develop N43D, partially compensates for the loss of stability, and we show that these residues likely form an ion pair. These data form a framework for understanding the impact of resistance mutations on viral fitness and pathogenesis and provide a pathway for the development of novel fusion inhibitor peptides. | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 11 09 | + | ==About this Structure== |
| + | 3CP1 is a [[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=3CP1 OCA]. | ||
| + | |||
| + | ==Reference== | ||
| + | Impact of the Enfuvirtide Resistance Mutation N43D and the Associated Baseline Polymorphism E137K on Peptide Sensitivity and Six-Helix Bundle Structure., Bai X, Wilson KL, Seedorff JE, Ahrens D, Green J, Davison DK, Jin L, Stanfield-Oakley SA, Mosier SM, Melby TE, Cammack N, Wang Z, Greenberg ML, Dwyer JJ, Biochemistry. 2008 May 29;. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18507398 18507398] | ||
| + | [[Category: Human immunodeficiency virus 1]] | ||
| + | [[Category: Single protein]] | ||
| + | [[Category: Dwyer, J J.]] | ||
| + | [[Category: Wang, Z M.]] | ||
| + | [[Category: 6-helix bundle]] | ||
| + | [[Category: Aid]] | ||
| + | [[Category: Apoptosis]] | ||
| + | [[Category: Coiled coil]] | ||
| + | [[Category: Envelope protein]] | ||
| + | [[Category: Fusion protein]] | ||
| + | [[Category: Gp41]] | ||
| + | [[Category: Hiv-1 envelope glycoprotein]] | ||
| + | [[Category: Host-virus interaction]] | ||
| + | [[Category: Membrane]] | ||
| + | [[Category: N43d]] | ||
| + | [[Category: Transmembrane]] | ||
| + | [[Category: Viral protein]] | ||
| + | [[Category: Virion]] | ||
| + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 18 12:11:09 2008'' | ||
Revision as of 09:11, 18 June 2008
Structure of a longer thermalstable core domain of HIV-1 gp41 containing the enfuvirtide resistance mutation N43D
Overview
Enfuvirtide (ENF), the first human immunodeficiency virus type 1 (HIV-1) fusion inhibitor approved for clinical use, acts by binding to gp41 heptad repeat 1 (HR1) and preventing its interaction with the viral HR2 region. Treatment-emergent resistance to ENF has been mapped to residues within HR1, and these mutations decrease its susceptibility to ENF and may reduce viral fitness and pathogenesis, although the mechanism for these effects is not clear. N43D, a common ENF resistance mutation, was found in in vitro assays to cause a 5-50-fold in antiviral activity. We introduced this mutation into peptide models and determined the impact of this mutation by circular dichroism and X-ray crystallography. We find that the mutation results in a decrease in the thermal stability of the six-helix bundle and causes a significant change in the HR1-HR2 interface, including a loss of HR2 helicity. These data form a mechanistic basis for the decrease in ENF sensitivity and six-helix bundle stability. The E137K polymorphism, generally present at baseline in patients who develop N43D, partially compensates for the loss of stability, and we show that these residues likely form an ion pair. These data form a framework for understanding the impact of resistance mutations on viral fitness and pathogenesis and provide a pathway for the development of novel fusion inhibitor peptides.
About this Structure
3CP1 is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
Reference
Impact of the Enfuvirtide Resistance Mutation N43D and the Associated Baseline Polymorphism E137K on Peptide Sensitivity and Six-Helix Bundle Structure., Bai X, Wilson KL, Seedorff JE, Ahrens D, Green J, Davison DK, Jin L, Stanfield-Oakley SA, Mosier SM, Melby TE, Cammack N, Wang Z, Greenberg ML, Dwyer JJ, Biochemistry. 2008 May 29;. PMID:18507398 Page seeded by OCA on Wed Jun 18 12:11:09 2008
