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6mkl

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<StructureSection load='6mkl' size='340' side='right'caption='[[6mkl]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
<StructureSection load='6mkl' size='340' side='right'caption='[[6mkl]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6mkl]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MKL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MKL FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6mkl]] 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=6MKL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MKL FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7OA:(3S,3aR,5R,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl+[(2S,3R)-4-[{[2-(cyclopropylamino)-1,3-benzothiazol-6-yl]sulfonyl}(2-methylpropyl)amino]-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]carbamate'>7OA</scene></td></tr>
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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]] 1.7&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tys|5tys]], [[4hla|4hla]], [[5tyr|5tyr]], [[6mk9|6mk9]]</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=7OA:(3S,3aR,5R,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl+[(2S,3R)-4-[{[2-(cyclopropylamino)-1,3-benzothiazol-6-yl]sulfonyl}(2-methylpropyl)amino]-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]carbamate'>7OA</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6mkl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mkl OCA], [http://pdbe.org/6mkl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mkl RCSB], [http://www.ebi.ac.uk/pdbsum/6mkl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mkl ProSAT]</span></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=6mkl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mkl OCA], [https://pdbe.org/6mkl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mkl RCSB], [https://www.ebi.ac.uk/pdbsum/6mkl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mkl ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/A0A4P8EW36_9HIV1 A0A4P8EW36_9HIV1]
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We attempted to select HIV-1 variants resistant to darunavir (DRV), which potently inhibits the enzymatic activity and dimerization of protease and has a high genetic barrier to HIV-1 development of resistance to DRV. We conducted selection using a mixture of 8 highly multi-protease inhibitor (PI)-resistant, DRV-susceptible clinical HIV-1 variants (HIV-1(MIX)) containing 9 to 14 PI resistance-associated amino acid substitutions in protease. HIV-1(MIX) became highly resistant to DRV, with a 50% effective concentration (EC(50)) approximately 333-fold greater than that against HIV-1(NL4-3). HIV-1(MIX) at passage 51 (HIV-1(MIX(P51))) replicated well in the presence of 5 muM DRV and contained 14 mutations. HIV-1(MIX(P51)) was highly resistant to amprenavir, indinavir, nelfinavir, ritonavir, lopinavir, and atazanavir and moderately resistant to saquinavir and tipranavir. HIV-1(MIX(P51)) had a resemblance with HIV-1(C) of the HIV-1(MIX) population, and selection using HIV-1(C) was also performed; however, its DRV resistance acquisition was substantially delayed. The H219Q and I223V substitutions in Gag, lacking in HIV-1(C(P51)), likely contributed to conferring a replication advantage on HIV-1(MIX(P51)) by reducing intravirion cyclophilin A content. HIV-1(MIX(P51)) apparently acquired the substitutions from another HIV-1 strain(s) of HIV-1(MIX) through possible homologous recombination. The present data suggest that the use of multiple drug-resistant HIV-1 isolates is of utility in selecting drug-resistant variants and that DRV would not easily permit HIV-1 to develop significant resistance; however, HIV-1 can develop high levels of DRV resistance when a variety of PI-resistant HIV-1 strains are generated, as seen in patients experiencing sequential PI failure, and ensuing homologous recombination takes place. HIV-1(MIX(P51)) should be useful in elucidating the mechanisms of HIV-1 resistance to DRV and related agents.
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In vitro selection of highly darunavir-resistant and replication-competent HIV-1 variants by using a mixture of clinical HIV-1 isolates resistant to multiple conventional protease inhibitors.,Koh Y, Amano M, Towata T, Danish M, Leshchenko-Yashchuk S, Das D, Nakayama M, Tojo Y, Ghosh AK, Mitsuya H J Virol. 2010 Nov;84(22):11961-9. doi: 10.1128/JVI.00967-10. Epub 2010 Sep 1. PMID:20810732<ref>PMID:20810732</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6mkl" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human immunodeficiency virus 1]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Das, D]]
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[[Category: Das D]]
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[[Category: Hayashi, H]]
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[[Category: Hayashi H]]
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[[Category: Mitsuya, H]]
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[[Category: Mitsuya H]]
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[[Category: Yedidi, R S]]
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[[Category: Yedidi RS]]
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[[Category: Darunavir-resistance]]
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[[Category: Grl-142]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Non-peptidic]]
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[[Category: P51]]
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[[Category: Protease-inhibitor complex]]
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Current revision

X-ray crystal structure of darunavir-resistant-P51 HIV-1 protease in complex with GRL-142

PDB ID 6mkl

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