2hs2

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[[Image:2hs2.gif|left|200px]]
[[Image:2hs2.gif|left|200px]]
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{{Structure
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|PDB= 2hs2 |SIZE=350|CAPTION= <scene name='initialview01'>2hs2</scene>, resolution 1.22&Aring;
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The line below this paragraph, containing "STRUCTURE_2hs2", creates the "Structure Box" on the page.
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|SITE=
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|LIGAND= <scene name='pdbligand=017:(3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE'>017</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|GENE= GAG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1])
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|DOMAIN=
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{{STRUCTURE_2hs2| PDB=2hs2 | SCENE= }}
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|RELATEDENTRY=[[2hs1|2HS1]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2hs2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hs2 OCA], [http://www.ebi.ac.uk/pdbsum/2hs2 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2hs2 RCSB]</span>
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'''Crystal structure of M46L mutant of HIV-1 protease complexed with TMC114 (darunavir)'''
'''Crystal structure of M46L mutant of HIV-1 protease complexed with TMC114 (darunavir)'''
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[[Category: Liu, F.]]
[[Category: Liu, F.]]
[[Category: Weber, I T.]]
[[Category: Weber, I T.]]
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[[Category: aspartic protease active site surface binding site]]
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[[Category: Aspartic protease active site surface binding site]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 06:38:43 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:34:36 2008''
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Revision as of 03:38, 4 May 2008

Image:2hs2.gif

Template:STRUCTURE 2hs2

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. 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 Page seeded by OCA on Sun May 4 06:38:43 2008

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