4nju

<StructureSection load='4nju' size='340' side='right' caption='[[4nju]], [[Resolution|resolution]] 1.80&Aring;' scene=''>

<table><tr><td colspan='2'>[[4nju]] 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=4NJU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NJU FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPV:N-(3-{(1R)-1-[(6R)-4-HYDROXY-2-OXO-6-PHENETHYL-6-PROPYL-5,6-DIHYDRO-2H-PYRAN-3-YL]PROPYL}PHENYL)-5-(TRIFLUOROMETHYL)-2-PYRIDINESULFONAMIDE'>TPV</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4nju FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nju OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4nju RCSB], [http://www.ebi.ac.uk/pdbsum/4nju PDBsum]</span></td></tr>

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== 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: &gt;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: &gt;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>

== References ==

[[Category: Das, D]]

[[Category: Garimella, H]]

[[Category: Kaufman, J D]]

[[Category: Mitsuya, H]]

[[Category: Wingfield, P T]]

[[Category: Yedidi, R S]]

[[Category: Hiv-1 protease]]

[[Category: Hydrolase-hydrolase inhibitor complex]]

[[Category: Tpv]]