2pym
From Proteopedia
(New page: 200px<br /><applet load="2pym" size="350" color="white" frame="true" align="right" spinBox="true" caption="2pym, resolution 1.90Å" /> '''HIV-1 PR mutant in c...) |
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| - | [[Image:2pym.jpg|left|200px]] | + | [[Image:2pym.jpg|left|200px]] |
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| - | '''HIV-1 PR mutant in complex with nelfinavir''' | + | {{Structure |
| + | |PDB= 2pym |SIZE=350|CAPTION= <scene name='initialview01'>2pym</scene>, resolution 1.90Å | ||
| + | |SITE= <scene name='pdbsite=AC1:1un+Binding+Site+For+Residue+A+1001'>AC1</scene> | ||
| + | |LIGAND= <scene name='pdbligand=1UN:2-[2-HYDROXY-3-(3-HYDROXY-2-METHYL-BENZOYLAMINO)-4-PHENYL SULFANYL-BUTYL]-DECAHYDRO-ISOQUINOLINE-3-CARBOXYLIC ACID TERT-BUTYLAMIDE'>1UN</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] | ||
| + | |GENE= gag-pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1]) | ||
| + | }} | ||
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| + | '''HIV-1 PR mutant in complex with nelfinavir''' | ||
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==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2PYM is a [ | + | 2PYM 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=2PYM OCA]. |
==Reference== | ==Reference== | ||
| - | Molecular analysis of the HIV-1 resistance development: enzymatic activities, crystal structures, and thermodynamics of nelfinavir-resistant HIV protease mutants., Kozisek M, Bray J, Rezacova P, Saskova K, Brynda J, Pokorna J, Mammano F, Rulisek L, Konvalinka J, J Mol Biol. 2007 Dec 7;374(4):1005-16. Epub 2007 Oct 3. PMID:[http:// | + | Molecular analysis of the HIV-1 resistance development: enzymatic activities, crystal structures, and thermodynamics of nelfinavir-resistant HIV protease mutants., Kozisek M, Bray J, Rezacova P, Saskova K, Brynda J, Pokorna J, Mammano F, Rulisek L, Konvalinka J, J Mol Biol. 2007 Dec 7;374(4):1005-16. Epub 2007 Oct 3. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17977555 17977555] |
[[Category: HIV-1 retropepsin]] | [[Category: HIV-1 retropepsin]] | ||
[[Category: Human immunodeficiency virus 1]] | [[Category: Human immunodeficiency virus 1]] | ||
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[[Category: resistance; nelfinavir]] | [[Category: resistance; nelfinavir]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:19:35 2008'' |
Revision as of 16:19, 20 March 2008
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| , resolution 1.90Å | |||||||
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| Sites: | |||||||
| Ligands: | |||||||
| Gene: | gag-pol (Human immunodeficiency virus 1) | ||||||
| Activity: | HIV-1 retropepsin, with EC number 3.4.23.16 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
HIV-1 PR mutant in complex with nelfinavir
Overview
Human immunodeficiency virus (HIV) encodes an aspartic protease (PR) that cleaves viral polyproteins into mature proteins, thus leading to the formation of infectious particles. Protease inhibitors (PIs) are successful virostatics. However, their efficiency is compromised by antiviral resistance. In the PR sequence of viral variants resistant to the PI nelfinavir, the mutations D30N and L90M appear frequently. However, these two mutations are seldom found together in vivo, suggesting that there are two alternative evolutionary pathways leading to nelfinavir resistance. Here we analyze the proteolytic activities, X-ray structures, and thermodynamics of inhibitor binding to HIV-1 PRs harboring the D30N and L90M mutations alone and in combination with other compensatory mutations. Vitality values obtained for recombinant mutant proteases and selected PR inhibitors confirm the crucial role of mutations in positions 30 and 90 for nelfinavir resistance. The combination of the D30N and L90M mutations significantly increases the enzyme vitality in the presence of nelfinavir, without a dramatic decrease in the catalytic efficiency of the recombinant enzyme. Crystal structures, molecular dynamics simulations, and calorimetric data for four mutants (D30N, D30N/A71V, D30N/N88D, and D30N/L90M) were used to augment our kinetic data. Calorimetric analysis revealed that the entropic contribution to the mutant PR/nelfinavir interaction is less favorable than the entropic contribution to the binding of nelfinavir by wild-type PR. This finding is supported by the structural data and simulations; nelfinavir binds most strongly to the wild-type protease, which has the lowest number of protein-ligand hydrogen bonds and whose structure exhibits the greatest degree of fluctuation upon inhibitor binding.
About this Structure
2PYM is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
Reference
Molecular analysis of the HIV-1 resistance development: enzymatic activities, crystal structures, and thermodynamics of nelfinavir-resistant HIV protease mutants., Kozisek M, Bray J, Rezacova P, Saskova K, Brynda J, Pokorna J, Mammano F, Rulisek L, Konvalinka J, J Mol Biol. 2007 Dec 7;374(4):1005-16. Epub 2007 Oct 3. PMID:17977555
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