2FD0

HIV-1 DIS kissing-loop in complex with lividomycin

Summary for 2FD0

• Entry DOI: 10.2210/pdb2fd0/pdb
• Related: 2FCX 2FCY 2FCZ
• Descriptor: HIV-1 DIS RNA, (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-(HYDROXYMET HYL)-TETRAHYDROFURAN-3-YLOXY)-4-HYDROXY-TETRAHYDRO-2H-PYRAN-3-YLOXY)-6-(HYDROXYMETHYL)-TETRAHYDRO-2H-PYRAN-3,4,5-TRIOL, POTASSIUM ION, ... (5 entities in total)
• Functional Keywords: hiv-1, rna, aminoglycoside, antibiotics
• Total number of polymer chains: 2
• Total formula weight: 16646.12

Authors

Ennifar, E.,Paillart, J.C.,Marquet, R.,Dumas, P. (deposition date: 2005-12-13, release date: 2006-05-16, Last modification date: 2023-08-30)

Primary citation

Ennifar, E.,Paillart, J.C.,Bodlenner, A.,Walter, P.,Weibel, J.-M.,Aubertin, A.-M.,Pale, P.,Dumas, P.,Marquet, R.
Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell.
Nucleic Acids Res., 34:2328-2339, 2006

PubMed Abstract: 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.

PubMed: 16679451
DOI: 10.1093/nar/gkl317

Experimental method

X-RAY DIFFRACTION (1.8 Å)