2f81: Difference between revisions

Revision as of 03:34, 4 May 2008

HIV-1 Protease mutant L90M complexed with inhibitor TMC114

OverviewOverview

The potent new antiviral inhibitor TMC-114 (UIC-94017) of HIV-1 protease (PR) has been studied with three PR variants containing single mutations D30N, I50V, and L90M, which provide resistance to the major clinical inhibitors. The inhibition constants (K(i)) of TMC-114 for mutants PR(D30N), PR(I50V), and PR(L90M) were 30-, 9-, and 0.14-fold, respectively, relative to wild-type PR. The molecular basis for the inhibition was analyzed using high-resolution (1.22-1.45 A) crystal structures of PR mutant complexes with TMC-114. In PR(D30N), the inhibitor has a water-mediated interaction with the side chain of Asn30 rather than the direct interaction observed in PR, which is consistent with the relative inhibition. Similarly, in PR(I50V) the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PR(L90M) structure compared to the PR structure, leading to a tighter binding of the inhibitor. The observed changes in PR structure and activity are discussed in relation to the potential for development of resistant mutants on exposure to TMC-114.

About this StructureAbout this Structure

2F81 is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.

ReferenceReference

Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M., Kovalevsky AY, Tie Y, Liu F, Boross PI, Wang YF, Leshchenko S, Ghosh AK, Harrison RW, Weber IT, J Med Chem. 2006 Feb 23;49(4):1379-87. PMID:16480273 Page seeded by OCA on Sun May 4 03:34:14 2008

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OCA

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 [[Image:2f81.gif|left|200px]]
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-|ACTIVITY= <span class='plainlinks'>[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] </span>
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-|GENE= 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 Protease mutant L90M complexed with inhibitor TMC114'''
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 [[Category: Kovalevsky, A Y.]]
 [[Category: Weber, I T.]]
-[[Category: hiv-1 protease-inhibitor complex]]
+[[Category: Hiv-1 protease-inhibitor complex]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 03:34:14 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:59:09 2008''