PDBsum entry 2fd0

RNA

PDB id: 2fd0

Contents

DNA/RNA

Ligands

LIV ×2

Metals

__K ×4

_CL

Waters ×90

PDB id:

2fd0

Name:

RNA

Title:

HIV-1 dis kissing-loop in complex with lividomycin

Structure:

HIV-1 dis RNA. Chain: a, b. Engineered: yes

Source:

Synthetic: yes. Other_details: this sequence occurs naturally in subtype f HIV-1

Biol. unit:

Dimer (from PQS)

Resolution:

1.80Å R-factor: 0.245 R-free: 0.245

Authors:

E.Ennifar,J.C.Paillart,R.Marquet,P.Dumas

Key ref:

E.Ennifar et al. (2006). Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell. Nucleic Acids Res, 34, 2328-2339. PubMed id: 16679451

Date:

13-Dec-05 Release date: 16-May-06

DNA/RNA chains

C-U-5BU-G-C-U-G-A-A-G-U-G-C-A-C-A-C-A-G-C-A-A-G 23 bases

C-U-5BU-G-C-U-G-A-A-G-U-G-C-A-C-A-C-A-G-C-A-A-G 23 bases

Nucleic Acids Res 34:2328-2339 (2006)

PubMed id: 16679451

Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell.

E.Ennifar, J.C.Paillart, A.Bodlenner, P.Walter, J.M.Weibel, A.M.Aubertin, P.Pale, P.Dumas, R.Marquet.

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.