2i4w: Difference between revisions

Revision as of 07:31, 29 July 2008

This article has been automatically seeded. Changes to this page should pertain to the PDB entry only and not to the protein or biomolecule in general.

File:2i4w.png

Template:STRUCTURE 2i4w

HIV-1 protease WT with GS-8374HIV-1 protease WT with GS-8374

Template:ABSTRACT PUBMED 16979654

About this StructureAbout this Structure

2I4W is a Single protein structure of sequence from Human immunodeficiency virus 1. 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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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

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-==Overview==
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-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.
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 ==About this Structure==
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 [[Category: Hiv-1 protease inhibitor]]
 [[Category: Hydrolase]]
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