2hs2: Difference between revisions

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New page: left|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 />
<applet load="2hs2" size="450" color="white" frame="true" align="right" spinBox="true"
caption="2hs2, resolution 1.22&Aring;" />
'''Crystal structure of M46L mutant of HIV-1 protease complexed with TMC114 (darunavir)'''<br />


==Overview==
==Crystal structure of M46L mutant of HIV-1 protease complexed with TMC114 (darunavir)==
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.
<StructureSection load='2hs2' size='340' side='right'caption='[[2hs2]], [[Resolution|resolution]] 1.22&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2hs2]] 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=2HS2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2HS2 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.22&#8491;</td></tr>
<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>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2hs2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hs2 OCA], [https://pdbe.org/2hs2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2hs2 RCSB], [https://www.ebi.ac.uk/pdbsum/2hs2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2hs2 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/Q7SSI0_9HIV1 Q7SSI0_9HIV1]
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hs/2hs2_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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=2hs2 ConSurf].
<div style="clear:both"></div>


==About this Structure==
==See Also==
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://ispc.weizmann.ac.il/oca-bin/ocashort?id=2HS2 OCA].
*[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]]
 
__TOC__
==Reference==
</StructureSection>
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]
[[Category: Human immunodeficiency virus 1]]
[[Category: Human immunodeficiency virus 1]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Kovalevsky, A.Y.]]
[[Category: Kovalevsky AY]]
[[Category: Liu, F.]]
[[Category: Liu F]]
[[Category: Weber, I.T.]]
[[Category: Weber IT]]
[[Category: 017]]
[[Category: CL]]
[[Category: DMS]]
[[Category: aspartic protease active site surface binding site]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Thu Nov  8 14:50:54 2007''

Latest revision as of 12:34, 14 February 2024

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)

Structural highlights

2hs2 is a 2 chain structure with sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.22Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q7SSI0_9HIV1

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

2hs2, resolution 1.22Å

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OCA
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