4njs: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<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>
<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" 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>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</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='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='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>
</table>
</table>
== Function ==
== Function ==
[https://www.uniprot.org/uniprot/Q9J006_9HIV1 Q9J006_9HIV1]  
[https://www.uniprot.org/uniprot/Q9J006_9HIV1 Q9J006_9HIV1]  
<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: &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>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4njs" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]]
*[[Immunodeficiency virus protease 3D structures|Immunodeficiency virus protease 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>

Latest revision as of 15:33, 1 March 2024

Crystal structure of multidrug-resistant clinical isolate A02 HIV-1 protease in complex with non-peptidic inhibitor, GRL008Crystal structure of multidrug-resistant clinical isolate A02 HIV-1 protease in complex with non-peptidic inhibitor, GRL008

Structural highlights

4njs is a 4 chain structure with sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.8Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q9J006_9HIV1

See Also

4njs, resolution 1.80Å

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