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4njs
From Proteopedia
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| - | + | ==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=''> | |
| + | == 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> | ||
| + | </td></tr><tr><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><br> | ||
| + | <tr><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><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><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://www.rcsb.org/pdb/explore.do?structureId=4njs RCSB], [http://www.ebi.ac.uk/pdbsum/4njs PDBsum]</span></td></tr> | ||
| + | <table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:24752271</ref> | |
| - | + | ||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: 9hiv1]] | ||
[[Category: Das, D.]] | [[Category: Das, D.]] | ||
[[Category: Garimella, H.]] | [[Category: Garimella, H.]] | ||
Revision as of 07:01, 21 May 2014
Crystal structure of multidrug-resistant clinical isolate A02 HIV-1 protease in complex with non-peptidic inhibitor, GRL008
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