2fd0: Difference between revisions
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==HIV-1 DIS kissing-loop in complex with lividomycin== | |||
<StructureSection load='2fd0' size='340' side='right'caption='[[2fd0]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2fd0]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FD0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2FD0 FirstGlance]. <br> | |||
</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5BU:5-BROMO-URIDINE-5-MONOPHOSPHATE'>5BU</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=LIV:(2R,3S,4S,5S,6R)-2-((2S,3S,4R,5R,6R)-5-AMINO-2-(AMINOMETHYL)-6-((2R,3S,4R,5S)-5-((1R,2R,3S,5R,6S)-3,5-DIAMINO-2-((2S,3R,5S,6R)-3-AMINO-5-HYDROXY-6-(HYDROXYMETHYL)-TETRAHYDRO-2H-PYRAN-2-YLOXY)-6-HYDROXYCYCLOHEXYLOXY)-4-HYDROXY-2-(HYDROXYMETHYL)-TETRAHYDROFURAN-3-YLOXY)-4-HYDROXY-TETRAHYDRO-2H-PYRAN-3-YLOXY)-6-(HYDROXYMETHYL)-TETRAHYDRO-2H-PYRAN-3,4,5-TRIOL'>LIV</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=2fd0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fd0 OCA], [https://pdbe.org/2fd0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2fd0 RCSB], [https://www.ebi.ac.uk/pdbsum/2fd0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2fd0 ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
== | |||
The kissing-loop complex that initiates dimerization of genomic RNA is crucial for Human Immunodeficiency Virus Type 1 (HIV-1) replication. We showed that owing to its strong similitude with the bacterial ribosomal A site it can be targeted by aminoglycosides. Here, we present its crystal structure in complex with neamine, ribostamycin, neomycin and lividomycin. These structures explain the specificity for 4,5-disubstituted 2-deoxystreptamine (DOS) derivatives and for subtype A and subtype F kissing-loop complexes, and provide a strong basis for rational drug design. As a consequence of the different topologies of the kissing-loop complex and the A site, these aminoglycosides establish more contacts with HIV-1 RNA than with 16S RNA. Together with biochemical experiments, they showed that while rings I, II and III confer binding specificity, rings IV and V are important for affinity. Binding of neomycin, paromomycin and lividomycin strongly stabilized the kissing-loop complex by bridging the two HIV-1 RNA molecules. Furthermore, in situ footprinting showed that the dimerization initiation site (DIS) of HIV-1 genomic RNA could be targeted by these aminoglycosides in infected cells and virions, demonstrating its accessibility. | The kissing-loop complex that initiates dimerization of genomic RNA is crucial for Human Immunodeficiency Virus Type 1 (HIV-1) replication. We showed that owing to its strong similitude with the bacterial ribosomal A site it can be targeted by aminoglycosides. Here, we present its crystal structure in complex with neamine, ribostamycin, neomycin and lividomycin. These structures explain the specificity for 4,5-disubstituted 2-deoxystreptamine (DOS) derivatives and for subtype A and subtype F kissing-loop complexes, and provide a strong basis for rational drug design. As a consequence of the different topologies of the kissing-loop complex and the A site, these aminoglycosides establish more contacts with HIV-1 RNA than with 16S RNA. Together with biochemical experiments, they showed that while rings I, II and III confer binding specificity, rings IV and V are important for affinity. Binding of neomycin, paromomycin and lividomycin strongly stabilized the kissing-loop complex by bridging the two HIV-1 RNA molecules. Furthermore, in situ footprinting showed that the dimerization initiation site (DIS) of HIV-1 genomic RNA could be targeted by these aminoglycosides in infected cells and virions, demonstrating its accessibility. | ||
Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell.,Ennifar E, Paillart JC, Bodlenner A, Walter P, Weibel JM, Aubertin AM, Pale P, Dumas P, Marquet R Nucleic Acids Res. 2006 May 5;34(8):2328-39. Print 2006. PMID:16679451<ref>PMID:16679451</ref> | |||
Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell., Ennifar E, Paillart JC, Bodlenner A, Walter P, Weibel JM, Aubertin AM, Pale P, Dumas P, Marquet R | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2fd0" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Dumas P]] | |||
[[Category: Ennifar E]] | |||
[[Category: Marquet R]] | |||
[[Category: Paillart JC]] | |||
