4YE2

The 1.35 structure of a viral RNase L antagonist reveals basis for the 2'-5'-oligoadenylate binding and enzyme activity.

Summary for 4YE2

• Entry DOI: 10.2210/pdb4ye2/pdb
• Related: 4RPT 4YFW 4YFZ 4YG0 4YG3 4YG6
• Descriptor: Capping enzyme protein, ADENOSINE-2'-5'-DIPHOSPHATE, SULFATE ION, ... (4 entities in total)
• Functional Keywords: innate immunity, rnase l, oligoadenylate, rotavirus, coronavirus, phosphodiesterase, viral protein
• Biological source: Rotavirus A
• Total number of polymer chains: 2
• Total formula weight: 34056.22

Authors

Hu, L.,Sankaran, B.,Prasad, B.V.V. (deposition date: 2015-02-23, release date: 2015-04-29, Last modification date: 2023-09-27)

Primary citation

Ogden, K.M.,Hu, L.,Jha, B.K.,Sankaran, B.,Weiss, S.R.,Silverman, R.H.,Patton, J.T.,Prasad, B.V.
Structural basis for 2'-5'-oligoadenylate binding and enzyme activity of a viral RNase L antagonist.
J.Virol., 89:6633-6645, 2015

PubMed Abstract: Synthesis of 2'-5'-oligoadenylates (2-5A) by oligoadenylate synthetase (OAS) is an important innate cellular response that limits viral replication by activating the latent cellular RNase, RNase L, to degrade single-stranded RNA. Some rotaviruses and coronaviruses antagonize the OAS/RNase L pathway through the activity of an encoded 2H phosphoesterase domain that cleaves 2-5A. These viral 2H phosphoesterases are phylogenetically related to the cellular A kinase anchoring protein 7 (AKAP7) and share a core structure and an active site that contains two well-defined HΦ(S/T)Φ (where Φ is a hydrophobic residue) motifs, but their mechanism of substrate binding is unknown. Here, we report the structures of a viral 2H phosphoesterase, the C-terminal domain (CTD) of the group A rotavirus (RVA) VP3 protein, both alone and in complex with 2-5A. The domain forms a compact fold, with a concave β-sheet that contains the catalytic cleft, but it lacks two α-helical regions and two β-strands observed in AKAP7 and other 2H phosphoesterases. The cocrystal structure shows significant conformational changes in the R loop upon ligand binding. Bioinformatics and biochemical analyses reveal that conserved residues and residues required for catalytic activity and substrate binding comprise the catalytic motifs and a region on one side of the binding cleft. We demonstrate that the VP3 CTD of group B rotavirus, but not that of group G, cleaves 2-5A. These findings suggest that the VP3 CTD is a streamlined version of a 2H phosphoesterase with a ligand-binding mechanism that is shared among 2H phosphodiesterases that cleave 2-5A.

PubMed: 25878106
DOI: 10.1128/JVI.00701-15

Experimental method

X-RAY DIFFRACTION (3.098 Å)