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2hs1

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[[Image:2hs1.gif|left|200px]]<br /><applet load="2hs1" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="2hs1, resolution 0.84&Aring;" />
 
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'''Ultra-high resolution X-ray crystal structure of HIV-1 protease V32I mutant with TMC114 (darunavir) inhibitor'''<br />
 
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==Overview==
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==Ultra-high resolution X-ray crystal structure of HIV-1 protease V32I mutant with TMC114 (darunavir) inhibitor==
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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.
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<StructureSection load='2hs1' size='340' side='right'caption='[[2hs1]], [[Resolution|resolution]] 0.84&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2hs1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HS1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HS1 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 0.84&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2hs1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hs1 OCA], [https://pdbe.org/2hs1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2hs1 RCSB], [https://www.ebi.ac.uk/pdbsum/2hs1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2hs1 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/Q7SSI0_9HIV1 Q7SSI0_9HIV1]
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hs/2hs1_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2hs1 ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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2HS1 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].
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*[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16962136 16962136]
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[[Category: HIV-1 retropepsin]]
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[[Category: Human immunodeficiency virus 1]]
[[Category: Human immunodeficiency virus 1]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Kovalevsky, A Y.]]
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[[Category: Kovalevsky AY]]
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[[Category: Weber, I T.]]
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[[Category: Weber IT]]
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[[Category: 017]]
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[[Category: CL]]
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[[Category: DMS]]
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[[Category: ultra-high resolution active site surface binding site]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:45:06 2008''
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Current revision

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

PDB ID 2hs1

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