2i4x: Difference between revisions
New page: left|200px<br /> <applet load="2i4x" size="450" color="white" frame="true" align="right" spinBox="true" caption="2i4x, resolution 1.55Å" /> '''HIV-1 Protease I84V... |
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[[Image:2i4x. | [[Image:2i4x.jpg|left|200px]]<br /><applet load="2i4x" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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'''HIV-1 Protease I84V, L90M with GS-8374'''<br /> | '''HIV-1 Protease I84V, L90M with GS-8374'''<br /> | ||
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==About this Structure== | ==About this Structure== | ||
2I4X 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] with KGQ as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http:// | 2I4X 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] with <scene name='pdbligand=KGQ:'>KGQ</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2I4X OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: hydrolase]] | [[Category: hydrolase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 13:51:45 2008'' | ||
Revision as of 14:51, 23 January 2008
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HIV-1 Protease I84V, L90M with GS-8374
OverviewOverview
The introduction of human immunodeficiency virus type 1 (HIV-1) protease, inhibitors (PIs) markedly improved the clinical outcome and control of, HIV-1 infection. However, cross-resistance among PIs due to a wide, spectrum of mutations in viral protease is a major factor limiting their, broader clinical use. Here we report on the suppression of PI resistance, using a covalent attachment of a phosphonic acid motif to a peptidomimetic, inhibitor scaffold. The resulting phosphonate analogs maintain high, binding affinity to HIV-1 protease, potent antiretroviral activity, and, unlike the parent molecules, display no loss of potency against a panel of, clinically important PI-resistant HIV-1 strains. As shown by, crystallographic analysis, the phosphonate moiety is highly exposed to, solvent with no discernable interactions with any of the enzyme active, site or surface residues. We term this effect "solvent anchoring" and, demonstrate that it is driven by a favorable change in the inhibitor, binding entropy upon the interaction with mutant enzymes. This type of, thermodynamic behavior, which was not found with the parent scaffold fully, buried in the enzyme active site, is a result of the increased degeneracy, of inhibitor binding states, allowing effective molecular adaptation to, the expanded cavity volume of mutant proteases. This strategy, which is, applicable to various PI scaffolds, should facilitate the design of novel, PIs and potentially other antiviral therapeutics.
About this StructureAbout this Structure
2I4X is a Single protein structure of sequence from Human immunodeficiency virus 1 with as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
ReferenceReference
Suppression of HIV-1 protease inhibitor resistance by phosphonate-mediated solvent anchoring., Cihlar T, He GX, Liu X, Chen JM, Hatada M, Swaminathan S, McDermott MJ, Yang ZY, Mulato AS, Chen X, Leavitt SA, Stray KM, Lee WA, J Mol Biol. 2006 Oct 27;363(3):635-47. Epub 2006 Aug 2. PMID:16979654
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