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| | ==Crystal structure of multidrug-resistant clinical isolate A02 HIV-1 protease in complex with non-peptidic inhibitor, GRL008== | | ==Crystal structure of multidrug-resistant clinical isolate A02 HIV-1 protease in complex with non-peptidic inhibitor, GRL008== |
| - | <StructureSection load='4njs' size='340' side='right' caption='[[4njs]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='4njs' size='340' side='right'caption='[[4njs]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4njs]] 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=4NJS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NJS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4njs]] 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=4NJS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NJS FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=G08:(3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL+[(2S,3R)-4-{[(4-CARBAMOYLPHENYL)SULFONYL](2-METHYLPROPYL)AMINO}-3-HYDROXY-1-PHENYLBUTAN-2-YL]CARBAMATE'>G08</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G08:(3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL+[(2S,3R)-4-{[(4-CARBAMOYLPHENYL)SULFONYL](2-METHYLPROPYL)AMINO}-3-HYDROXY-1-PHENYLBUTAN-2-YL]CARBAMATE'>G08</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4njt|4njt]], [[4nju|4nju]], [[4njv|4njv]], [[4i8z|4i8z]], [[4hla|4hla]], [[4i8w|4i8w]]</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=4njs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4njs OCA], [https://pdbe.org/4njs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4njs RCSB], [https://www.ebi.ac.uk/pdbsum/4njs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4njs ProSAT]</span></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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4njs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4njs OCA], [http://pdbe.org/4njs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4njs RCSB], [http://www.ebi.ac.uk/pdbsum/4njs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4njs ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/Q9J006_9HIV1 Q9J006_9HIV1] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4njs" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4njs" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Das, D]] | + | [[Category: Human immunodeficiency virus 1]] |
| - | [[Category: Garimella, H]] | + | [[Category: Large Structures]] |
| - | [[Category: Ghosh, A K]] | + | [[Category: Das D]] |
| - | [[Category: Kaufman, J D]]
| + | [[Category: Garimella H]] |
| - | [[Category: Mitsuya, H]] | + | [[Category: Ghosh AK]] |
| - | [[Category: Wingfield, P T]] | + | [[Category: Kaufman JD]] |
| - | [[Category: Yedidi, R S]] | + | [[Category: Mitsuya H]] |
| - | [[Category: Darunavir analog]] | + | [[Category: Wingfield PT]] |
| - | [[Category: Hiv-1 protease]] | + | [[Category: Yedidi RS]] |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]] | + | |
| - | [[Category: Multidrug-resistance]]
| + | |
| - | [[Category: Non-peptidic inhibitor]]
| + | |
| - | [[Category: Protease inhibitor]]
| + | |
| Structural highlights
Function
Q9J006_9HIV1
Publication Abstract from PubMed
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.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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. 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. Antimicrob Agents Chemother. 2014 Apr 21. PMID:24752271 doi:http://dx.doi.org/10.1128/AAC.00107-14
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