2hs2
From Proteopedia
(New page: 200px<br /> <applet load="2hs2" size="450" color="white" frame="true" align="right" spinBox="true" caption="2hs2, resolution 1.22Å" /> '''Crystal structure o...) |
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| - | [[Image:2hs2.gif|left|200px]]<br /> | + | [[Image:2hs2.gif|left|200px]]<br /><applet load="2hs2" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="2hs2, resolution 1.22Å" /> | caption="2hs2, resolution 1.22Å" /> | ||
'''Crystal structure of M46L mutant of HIV-1 protease complexed with TMC114 (darunavir)'''<br /> | '''Crystal structure of M46L mutant of HIV-1 protease complexed with TMC114 (darunavir)'''<br /> | ||
==Overview== | ==Overview== | ||
| - | TMC114 (darunavir) is a promising clinical inhibitor of HIV-1 protease | + | TMC114 (darunavir) is a promising clinical inhibitor of HIV-1 protease (PR) for treatment of drug resistant HIV/AIDS. We report the ultra-high 0.84 A resolution crystal structure of the TMC114 complex with PR containing the drug-resistant mutation V32I (PR(V32I)), and the 1.22 A resolution structure of a complex with PR(M46L). These structures show TMC114 bound at two distinct sites, one in the active-site cavity and the second on the surface of one of the flexible flaps in the PR dimer. Remarkably, TMC114 binds at these two sites simultaneously in two diastereomers related by inversion of the sulfonamide nitrogen. Moreover, the flap site is shaped to accommodate the diastereomer with the S-enantiomeric nitrogen rather than the one with the R-enantiomeric nitrogen. The existence of the second binding site and two diastereomers suggest a mechanism for the high effectiveness of TMC114 on drug-resistant HIV and the potential design of new inhibitors. |
==About this Structure== | ==About this Structure== | ||
| - | 2HS2 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 CL, 017 and DMS as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 2HS2 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=CL:'>CL</scene>, <scene name='pdbligand=017:'>017</scene> and <scene name='pdbligand=DMS:'>DMS</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HS2 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: Liu, F.]] | [[Category: Liu, F.]] | ||
| - | [[Category: Weber, I | + | [[Category: Weber, I T.]] |
[[Category: 017]] | [[Category: 017]] | ||
[[Category: CL]] | [[Category: CL]] | ||
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[[Category: aspartic protease active site surface binding site]] | [[Category: aspartic protease active site surface binding site]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:45:08 2008'' |
Revision as of 15:45, 21 February 2008
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Crystal structure of M46L mutant of HIV-1 protease complexed with TMC114 (darunavir)
Overview
TMC114 (darunavir) is a promising clinical inhibitor of HIV-1 protease (PR) for treatment of drug resistant HIV/AIDS. We report the ultra-high 0.84 A resolution crystal structure of the TMC114 complex with PR containing the drug-resistant mutation V32I (PR(V32I)), and the 1.22 A resolution structure of a complex with PR(M46L). These structures show TMC114 bound at two distinct sites, one in the active-site cavity and the second on the surface of one of the flexible flaps in the PR dimer. Remarkably, TMC114 binds at these two sites simultaneously in two diastereomers related by inversion of the sulfonamide nitrogen. Moreover, the flap site is shaped to accommodate the diastereomer with the S-enantiomeric nitrogen rather than the one with the R-enantiomeric nitrogen. The existence of the second binding site and two diastereomers suggest a mechanism for the high effectiveness of TMC114 on drug-resistant HIV and the potential design of new inhibitors.
About this Structure
2HS2 is a Single protein structure of sequence from Human immunodeficiency virus 1 with , and as ligands. Full crystallographic information is available from OCA.
Reference
Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114., Kovalevsky AY, Liu F, Leshchenko S, Ghosh AK, Louis JM, Harrison RW, Weber IT, J Mol Biol. 2006 Oct 13;363(1):161-73. Epub 2006 Aug 4. PMID:16962136
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