2f81: Difference between revisions
New page: left|200px<br /> <applet load="2f81" size="450" color="white" frame="true" align="right" spinBox="true" caption="2f81, resolution 1.25Å" /> '''HIV-1 Protease muta... |
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[[Image:2f81.gif|left|200px]]<br /> | [[Image:2f81.gif|left|200px]]<br /><applet load="2f81" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="2f81, resolution 1.25Å" /> | caption="2f81, resolution 1.25Å" /> | ||
'''HIV-1 Protease mutant L90M complexed with inhibitor TMC114'''<br /> | '''HIV-1 Protease mutant L90M complexed with inhibitor TMC114'''<br /> | ||
==Overview== | ==Overview== | ||
The potent new antiviral inhibitor TMC-114 (UIC-94017) of HIV-1 protease | 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 Structure== | ==About this Structure== | ||
2F81 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 NA, CL, 017 and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. 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:// | 2F81 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=NA:'>NA</scene>, <scene name='pdbligand=CL:'>CL</scene>, <scene name='pdbligand=017:'>017</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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=2F81 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Human immunodeficiency virus 1]] | [[Category: Human immunodeficiency virus 1]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Kovalevsky, A | [[Category: Kovalevsky, A Y.]] | ||
[[Category: Weber, I | [[Category: Weber, I T.]] | ||
[[Category: 017]] | [[Category: 017]] | ||
[[Category: CL]] | [[Category: CL]] | ||
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[[Category: hiv-1 protease-inhibitor complex]] | [[Category: hiv-1 protease-inhibitor complex]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:18:39 2008'' | ||
Revision as of 18:18, 21 February 2008
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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 with , , and as ligands. Active as HIV-1 retropepsin, with EC number 3.4.23.16 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
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