4NRU
Murine Norovirus RNA-dependent-RNA-polymerase in complex with Compound 6, a suramin derivative
Summary for 4NRU
| Entry DOI | 10.2210/pdb4nru/pdb |
| Descriptor | RNA dependent RNA polymerase, 4-({4-methyl-3-[(3-nitrobenzoyl)amino]benzoyl}amino)naphthalene-1,5-disulfonic acid, MAGNESIUM ION, ... (4 entities in total) |
| Functional Keywords | rna dependent rna polymerase, murine norovirus, viral protein-transcription inhibitor complex, viral protein/transcription inhibitor |
| Biological source | Murine norovirus 1 |
| Total number of polymer chains | 6 |
| Total formula weight | 354857.30 |
| Authors | Milani, M.,Croci, R.,Pezzullo, M.,Tarantino, D.,Mastrangelo, E.,Bolognesi, M. (deposition date: 2013-11-27, release date: 2014-10-15, Last modification date: 2024-11-27) |
| Primary citation | Croci, R.,Pezzullo, M.,Tarantino, D.,Milani, M.,Tsay, S.C.,Sureshbabu, R.,Tsai, Y.J.,Mastrangelo, E.,Rohayem, J.,Bolognesi, M.,Hwu, J.R. Structural bases of norovirus RNA dependent RNA polymerase inhibition by novel suramin-related compounds. Plos One, 9:e91765-e91765, 2014 Cited by PubMed Abstract: Noroviruses (NV) are +ssRNA viruses responsible for severe gastroenteritis; no effective vaccines/antivirals are currently available. We previously identified Suramin (9) as a potent inhibitor of NV-RNA dependent RNA polymerase (NV-RdRp). Despite significant in vitro activities versus several pharmacological targets, Suramin clinical use is hampered by pharmacokinetics/toxicity problems. To improve Suramin access to NV-RdRp in vivo, a Suramin-derivative, 8, devoid of two sulphonate groups, was synthesized, achieving significant anti-human-NV-RdRp activity (IC50 = 28 nM); the compound inhibits also murine NV (mNV) RdRp. The synthesis process led to the isolation/characterization of lower molecular weight intermediates (3-7) hosting only one sulphonate head. The crystal structures of both hNV/mNV-RdRps in complex with 6, were analyzed, providing new knowledge on the interactions that a small fragment can establish with NV-RdRps, and establishing a platform for structure-guided optimization of potency, selectivity and drugability. PubMed: 24622391DOI: 10.1371/journal.pone.0091765 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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