PDBsum entry 4zc7

RNA

PDB id: 4zc7

Contents

DNA/RNA

Ligands

PAR ×2

Waters ×4

PDB id:

4zc7

Name:

RNA

Title:

Paromomycin bound to a leishmanial ribosomal a-site

Structure:

RNA duplex. Chain: a, b, c, d. Engineered: yes

Source:

Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Resolution:

3.04Å R-factor: 0.191 R-free: 0.261

Authors:

M.Shalev,H.Rozenberg,C.L.Jaffe,N.Adir,T.Baasov

Key ref:

M.Shalev et al. (2015). Structural basis for selective targeting of leishmanial ribosomes: aminoglycoside derivatives as promising therapeutics. Nucleic Acids Res, 43, 8601-8613. PubMed id: 26264664 DOI: 10.1093/nar/gkv821

Date:

15-Apr-15 Release date: 26-Aug-15

DNA/RNA chains

G-C-G-U-C-G-U-U-C-C-G-G-A-A-A-A-G-U-C-G-C 21 bases

G-C-G-U-C-G-U-U-C-C-G-G-A-A-A-G-U-C-G-C 20 bases

G-C-G-U-C-G-U-U-C-C-G-G-A-A-A-A-G-U-C-G-C 21 bases

G-C-G-U-C-G-U-U-C-C-G-G-A-A-A-G-U-C-G-C 20 bases

DOI no: 10.1093/nar/gkv821

Nucleic Acids Res 43:8601-8613 (2015)

PubMed id: 26264664

Structural basis for selective targeting of leishmanial ribosomes: aminoglycoside derivatives as promising therapeutics.

M.Shalev, H.Rozenberg, B.Smolkin, A.Nasereddin, D.Kopelyanskiy, V.Belakhov, T.Schrepfer, J.Schacht, C.L.Jaffe, N.Adir, T.Baasov.

ABSTRACT

Leishmaniasis comprises an array of diseases caused by pathogenic species of Leishmania, resulting in a spectrum of mild to life-threatening pathologies. Currently available therapies for leishmaniasis include a limited selection of drugs. This coupled with the rather fast emergence of parasite resistance, presents a dire public health concern. Paromomycin (PAR), a broad-spectrum aminoglycoside antibiotic, has been shown in recent years to be highly efficient in treating visceral leishmaniasis (VL)-the life-threatening form of the disease. While much focus has been given to exploration of PAR activities in bacteria, its mechanism of action in Leishmania has received relatively little scrutiny and has yet to be fully deciphered. In the present study we present an X-ray structure of PAR bound to rRNA model mimicking its leishmanial binding target, the ribosomal A-site. We also evaluate PAR inhibitory actions on leishmanial growth and ribosome function, as well as effects on auditory sensory cells, by comparing several structurally related natural and synthetic aminoglycoside derivatives. The results provide insights into the structural elements important for aminoglycoside inhibitory activities and selectivity for leishmanial cytosolic ribosomes, highlighting a novel synthetic derivative, compound 3: , as a prospective therapeutic candidate for the treatment of VL.