2p3b

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[[Image:2p3b.gif|left|200px]]<br /><applet load="2p3b" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="2p3b, resolution 2.100&Aring;" />
 
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'''Crystal Structure of the subtype B wild type HIV protease complexed with TL-3 inhibitor'''<br />
 
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==Overview==
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==Crystal Structure of the subtype B wild type HIV protease complexed with TL-3 inhibitor==
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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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<StructureSection load='2p3b' size='340' side='right'caption='[[2p3b]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2p3b]] 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=2P3B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2P3B 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]] 2.1&#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=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>, <scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</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=2p3b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2p3b OCA], [https://pdbe.org/2p3b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2p3b RCSB], [https://www.ebi.ac.uk/pdbsum/2p3b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2p3b ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/Q9Q2G8_9HIV1 Q9Q2G8_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/p3/2p3b_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=2p3b ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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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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:17467738<ref>PMID:17467738</ref>
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2P3B is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] with <scene name='pdbligand=3TL:'>3TL</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. 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=2P3B OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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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://ispc.weizmann.ac.il//pmbin/getpm?pmid=17467738 17467738]
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</div>
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[[Category: HIV-1 retropepsin]]
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<div class="pdbe-citations 2p3b" style="background-color:#fffaf0;"></div>
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[[Category: Human immunodeficiency virus 1]]
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[[Category: Protein complex]]
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[[Category: Gustchina, A.]]
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[[Category: Krauchenco, S.]]
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[[Category: Martins, N.H.]]
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[[Category: Polikarpov, I.]]
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[[Category: Sanches, M.]]
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[[Category: Wlodawer, A.]]
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[[Category: 3TL]]
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[[Category: protease-inhibitor complex]]
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[[Category: tl-3 inhibitor]]
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[[Category: wild type subtype b hiv protease]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:05:11 2008''
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==See Also==
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*[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Human immunodeficiency virus 1]]
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[[Category: Large Structures]]
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[[Category: Gustchina A]]
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[[Category: Krauchenco S]]
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[[Category: Martins NH]]
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[[Category: Polikarpov I]]
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[[Category: Sanches M]]
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[[Category: Wlodawer A]]

Current revision

Crystal Structure of the subtype B wild type HIV protease complexed with TL-3 inhibitor

PDB ID 2p3b

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