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==Crystal Structure of the multi-drug resistant mutant subtype B HIV protease complexed with TL-3 inhibitor== | |||
<StructureSection load='2p3a' size='340' side='right'caption='[[2p3a]], [[Resolution|resolution]] 1.75Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2p3a]] 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=2P3A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2P3A 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]] 1.75Å</td></tr> | |||
<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> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2p3a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2p3a OCA], [https://pdbe.org/2p3a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2p3a RCSB], [https://www.ebi.ac.uk/pdbsum/2p3a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2p3a ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q6BB74_9HIV1 Q6BB74_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/p3/2p3a_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=2p3a ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2p3a" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]] | |||
[[Category: | == References == | ||
[[Category: Gustchina | <references/> | ||
[[Category: Krauchenco | __TOC__ | ||
[[Category: Martins | </StructureSection> | ||
[[Category: Polikarpov | [[Category: Human immunodeficiency virus 1]] | ||
[[Category: Sanches | [[Category: Large Structures]] | ||
[[Category: Wlodawer | [[Category: Gustchina A]] | ||
[[Category: Krauchenco S]] | |||
[[Category: Martins NH]] | |||
[[Category: Polikarpov I]] | |||
[[Category: Sanches M]] | |||
[[Category: Wlodawer A]] | |||
Latest revision as of 11:27, 30 October 2024
Crystal Structure of the multi-drug resistant mutant subtype B HIV protease complexed with TL-3 inhibitorCrystal Structure of the multi-drug resistant mutant subtype B HIV protease complexed with TL-3 inhibitor
Structural highlights
FunctionEvolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedAlthough 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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