2hs1: Difference between revisions

Revision as of 18:45, 21 February 2008

Ultra-high resolution X-ray crystal structure of HIV-1 protease V32I mutant with TMC114 (darunavir) inhibitor

OverviewOverview

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 StructureAbout this Structure

2HS1 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

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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OCA

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-[[Image:2hs1.gif|left|200px]]<br />
+[[Image:2hs1.gif|left|200px]]<br /><applet load="2hs1" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="2hs1" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="2hs1, resolution 0.84&Aring;" />
 '''Ultra-high resolution X-ray crystal structure of HIV-1 protease V32I mutant with TMC114 (darunavir) inhibitor'''<br />
 ==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.
+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==
-HS1 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]. 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=2HS1 OCA].
+HS1 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]. 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=2HS1 OCA].
 ==Reference==
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 [[Category: Human immunodeficiency virus 1]]
 [[Category: Single protein]]
-[[Category: Kovalevsky, A.Y.]]
+[[Category: Kovalevsky, A Y.]]
-[[Category: Weber, I.T.]]
+[[Category: Weber, I T.]]
 [[Category: 017]]
 [[Category: CL]]
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 [[Category: ultra-high resolution active site surface binding site]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Thu Nov  8 14:50:48 2007''
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