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| | ==Crystal structure of multidrug-resistant clinical isolate A02 HIV-1 protease in complex with ritonavir== | | ==Crystal structure of multidrug-resistant clinical isolate A02 HIV-1 protease in complex with ritonavir== |
| - | <StructureSection load='4njv' size='340' side='right' caption='[[4njv]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='4njv' size='340' side='right'caption='[[4njv]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4njv]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/9hiv1 9hiv1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NJV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NJV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4njv]] is a 4 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=4NJV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NJV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=RIT:RITONAVIR'>RIT</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4njs|4njs]], [[4njt|4njt]], [[4nju|4nju]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RIT:RITONAVIR'>RIT</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 9HIV1])</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=4njv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4njv OCA], [https://pdbe.org/4njv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4njv RCSB], [https://www.ebi.ac.uk/pdbsum/4njv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4njv ProSAT]</span></td></tr> |
| - | <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=4njv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4njv OCA], [http://pdbe.org/4njv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4njv RCSB], [http://www.ebi.ac.uk/pdbsum/4njv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4njv ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/Q9J006_9HIV1 Q9J006_9HIV1] |
| - | In the present study, GRL008, a novel non-peptidic human immunodeficiency virus type-1 (HIV-1) protease inhibitor (PI) and darunavir (DRV), both containing a P2-bis-tetrahydrofuranyl urethane (bis-THF) moiety, exert potent antiviral activity (EC50: 0.029 and 0.002 muM, respectively) against a multidrug-resistant clinical isolate of HIV-1 (HIVA02), compared to ritonavir (RTV) (EC50: >1.0 muM) and tipranavir (TPV) (EC50: 0.364 muM). Additionally, GRL008 showed potent antiviral activity against an HIV-1 variant selected with DRV over 20 passages (HIVDRVRP20) with a 2.6-fold increase in its EC50 (EC50: 0.097 muM) compared to its corresponding EC50 (EC50: 0.038 muM) against wild type HIV-1NL4-3 (HIVWT). In X-ray crystallographic analysis, both GRL008 and DRV showed strong hydrogen bonds (H-bonds) with the backbone amide-nitrogen/carbonyl-oxygen atoms of conserved active site amino acids, G27, D29, D30 and D30', of HIVA02 protease (PRA02) and wild type PR, in their corresponding crystal structures while TPV lacked H-bonds with G27 and D30' due to absence of polar groups. The P2' thiazolyl moiety of RTV showed two conformations in the crystal structure of PRA02-RTV complex, one of which showed loss of contacts in the S2' binding pocket of PRA02, supporting RTV's compromised antiviral data (EC50: >1 muM). Thus, conserved H-bonding network of P2-bis-THF-containing GRL008 with the backbone of G27, D29, D30 and D30' most likely contribute to its persistently greater antiviral activity against HIVWT, HIVA02, and HIVDRVRP20.
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| - | Conserved hydrogen-bonding network of P2 bis-tetrahydrofuran containing HIV-1 protease inhibitors (PI) with protease active site amino acid-backbone aid in their activity against PI-resistant HIV.,Yedidi RS, Garimella H, Aoki M, Aoki H, Desai DV, Chang SB, Davis DA, Fyvie WS, Kaufman JD, Smith DW, Das D, Wingfield PT, Maeda K, Ghosh AK, Mitsuya H Antimicrob Agents Chemother. 2014 Apr 21. PMID:24752271<ref>PMID:24752271</ref>
| + | ==See Also== |
| - | | + | *[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 4njv" style="background-color:#fffaf0;"></div>
| + | |
| - | == References ==
| + | |
| - | <references/>
| + | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Chang, S B]] | + | [[Category: Human immunodeficiency virus 1]] |
| - | [[Category: Das, D]] | + | [[Category: Large Structures]] |
| - | [[Category: Garimella, H]] | + | [[Category: Chang SB]] |
| - | [[Category: Kaufman, J D]] | + | [[Category: Das D]] |
| - | [[Category: Mitsuya, H]] | + | [[Category: Garimella H]] |
| - | [[Category: Wingfield, P T]] | + | [[Category: Kaufman JD]] |
| - | [[Category: Yedidi, R S]] | + | [[Category: Mitsuya H]] |
| - | [[Category: Hiv-1 protease]] | + | [[Category: Wingfield PT]] |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]] | + | [[Category: Yedidi RS]] |
| - | [[Category: Kaletra]]
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| - | [[Category: Multidrug-resistance]]
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| - | [[Category: Protease inhibitor]]
| + | |
| - | [[Category: Rit]]
| + | |
| - | [[Category: Ritonavir]]
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