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| [[Image:2p3d.gif|left|200px]]
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| {{Structure
| | ==Crystal Structure of the multi-drug resistant mutant subtype F HIV protease complexed with TL-3 inhibitor== |
| |PDB= 2p3d |SIZE=350|CAPTION= <scene name='initialview01'>2p3d</scene>, resolution 2.80Å
| | <StructureSection load='2p3d' size='340' side='right'caption='[[2p3d]], [[Resolution|resolution]] 2.80Å' scene=''> |
| |SITE= | | == Structural highlights == |
| |LIGAND= <scene name='pdbligand=3TL:BENZYL+(2S,5S,8S,9R,10R,11S,14S,17S)-8,11-DIBENZYL-9,10-DIHYDROXY-5,14-DIISOPROPYL-3,6,13,16-TETRAOXO-4,7,12,15-TETRAAZAOCTADECANE-2,17-DIYLDICARBAMATE'>3TL</scene>
| | <table><tr><td colspan='2'>[[2p3d]] 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=2P3D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2P3D FirstGlance]. <br> |
| |ACTIVITY= <span class='plainlinks'>[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] </span>
| | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8Å</td></tr> |
| |GENE=
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3TL:BENZYL+[(1S,4S,7S,8R,9R,10S,13S,16S)-7,10-DIBENZYL-8,9-DIHYDROXY-1,16-DIMETHYL-4,13-BIS(1-METHYLETHYL)-2,5,12,15,18-PENTAOXO-20-PHENYL-19-OXA-3,6,11,14,17-PENTAAZAICOS-1-YL]CARBAMATE'>3TL</scene></td></tr> |
| |DOMAIN=
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2p3d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2p3d OCA], [https://pdbe.org/2p3d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2p3d RCSB], [https://www.ebi.ac.uk/pdbsum/2p3d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2p3d ProSAT]</span></td></tr> |
| |RELATEDENTRY=[[2p3a|2P3A]], [[2p3b|2P3B]], [[2p3c|2P3C]]
| | </table> |
| |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2p3d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2p3d OCA], [http://www.ebi.ac.uk/pdbsum/2p3d PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2p3d RCSB]</span>
| | == Function == |
| }}
| | [https://www.uniprot.org/uniprot/Q7SRY5_9HIV1 Q7SRY5_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/p3/2p3d_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=2p3d ConSurf]. |
| | <div style="clear:both"></div> |
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| '''Crystal Structure of the multi-drug resistant mutant subtype F HIV protease complexed with TL-3 inhibitor'''
| | ==See Also== |
| | | *[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]] |
| | | __TOC__ |
| ==Overview== | | </StructureSection> |
| Although a majority of HIV-1 infections in Brazil are caused by the subtype B virus (also prevalent in the United States and Western Europe), viral subtypes F and C are also found very frequently. Genomic differences between the subtypes give rise to sequence variations in the encoded proteins, including the HIV-1 protease. The current anti-HIV drugs have been developed primarily against subtype B and the effects arising from the combination of drug-resistance mutations with the naturally existing polymorphisms in non-B HIV-1 subtypes are only beginning to be elucidated. To gain more insights into the structure and function of different variants of HIV proteases, we have determined a 2.1 A structure of the native subtype F HIV-1 protease (PR) in complex with the protease inhibitor TL-3. We have also solved crystal structures of two multi-drug resistant mutant HIV PRs in complex with TL-3, from subtype B (Bmut) carrying the primary mutations V82A and L90M, and from subtype F (Fmut) carrying the primary mutation V82A plus the secondary mutation M36I, at 1.75 A and 2.8 A resolution, respectively. The proteases Bmut, Fwt and Fmut exhibit sevenfold, threefold, and 54-fold resistance to TL-3, respectively. In addition, the structure of subtype B wild type HIV-PR in complex with TL-3 has been redetermined in space group P6(1), consistent with the other three structures. Our results show that the primary mutation V82A causes the known effect of collapsing the S1/S1' pockets that ultimately lead to the reduced inhibitory effect of TL-3. Our results further indicate that two naturally occurring polymorphic substitutions in subtype F and other non-B HIV proteases, M36I and L89M, may lead to early development of drug resistance in patients infected with non-B HIV subtypes.
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| ==About this Structure==
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| 2P3D is a [[Protein complex]] structure of sequences from [http://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=2P3D OCA].
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| ==Reference==
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| Structural characterization of B and non-B subtypes of HIV-protease: insights into the natural susceptibility to drug resistance development., Sanches M, Krauchenco S, Martins NH, Gustchina A, Wlodawer A, Polikarpov I, J Mol Biol. 2007 Jun 15;369(4):1029-40. Epub 2007 Mar 24. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17467738 17467738]
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| [[Category: HIV-1 retropepsin]]
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| [[Category: Human immunodeficiency virus 1]] | | [[Category: Human immunodeficiency virus 1]] |
| [[Category: Protein complex]] | | [[Category: Large Structures]] |
| [[Category: Gustchina, A.]] | | [[Category: Gustchina A]] |
| [[Category: Krauchenco, S.]] | | [[Category: Krauchenco S]] |
| [[Category: Martins, N H.]] | | [[Category: Martins NH]] |
| [[Category: Polikarpov, I.]] | | [[Category: Polikarpov I]] |
| [[Category: Sanches, M.]] | | [[Category: Sanches M]] |
| [[Category: Wlodawer, A.]] | | [[Category: Wlodawer A]] |
| [[Category: multi-drug resistant mutant subtype f hiv protease]]
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| [[Category: non-b hiv protease]]
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| [[Category: protease-inhibitor complex]]
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| [[Category: tl-3 inhibitor]]
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| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:28:27 2008''
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