5IQ6

Crystal structure of Dengue virus serotype 3 RNA dependent RNA polymerase bound to HeE1-2Tyr, a new pyridobenzothizole inhibitor

Summary for 5IQ6

• Entry DOI: 10.2210/pdb5iq6/pdb
• Descriptor: RNA dependent RNA polymerase, ZINC ION, N-[8-(cyclohexyloxy)-1-oxo-2-phenyl-1H-pyrido[2,1-b][1,3]benzothiazole-4-carbonyl]-L-tyrosine, ... (4 entities in total)
• Functional Keywords: rna dependent rna polymerase, hydrolase
• Biological source: Dengue virus 3
• Cellular location: Virion membrane ; Multi-pass membrane protein : Q6DLV0
• Total number of polymer chains: 1
• Total formula weight: 73582.53

Authors

Tarantino, D.,Mastrangelo, E.,Milani, M. (deposition date: 2016-03-10, release date: 2016-10-05, Last modification date: 2024-05-08)

Primary citation

Tarantino, D.,Cannalire, R.,Mastrangelo, E.,Croci, R.,Querat, G.,Barreca, M.L.,Bolognesi, M.,Manfroni, G.,Cecchetti, V.,Milani, M.
Targeting flavivirus RNA dependent RNA polymerase through a pyridobenzothiazole inhibitor.
Antiviral Res., 134:226-235, 2016

PubMed Abstract: RNA dependent RNA polymerases (RdRp) are essential enzymes for flavivirus replication. Starting from an in silico docking analysis we identified a pyridobenzothiazole compound, HeE1-2Tyr, able to inhibit West Nile and Dengue RdRps activity in vitro, which proved effective against different flaviviruses in cell culture. Crystallographic data show that HeE1-2Tyr binds between the fingers domain and the priming loop of Dengue virus RdRp (Site 1). Conversely, enzyme kinetics, binding studies and mutational analyses suggest that, during the catalytic cycle and assembly of the RdRp-RNA complex, HeE1-2Tyr might be hosted in a distinct binding site (Site 2). RdRp mutational studies, driven by in silico docking analysis, allowed us to locate the inhibition Site 2 in the thumb domain. Taken together, our results provide innovative concepts for optimization of a new class of anti-flavivirus compounds.

PubMed: 27649989
DOI: 10.1016/j.antiviral.2016.09.007

Experimental method

X-RAY DIFFRACTION (3 Å)