SNAP output for PDB entry 4ig8 [SNAP web server]

PDB-id

4ig8; SNAP-derived features in text and JSON formats; DNAproDB

Class

transferase-RNA

Method

X-ray (2.7 Å)

Summary

Structural basis for cytosolic double-stranded RNA surveillance by human oas1

Reference

Donovan J, Dufner M, Korennykh A (2013): "Structural basis for cytosolic double-stranded RNA surveillance by human oligoadenylate synthetase 1." Proc.Natl.Acad.Sci.USA, 110, 1652-1657. doi: 10.1073/pnas.1218528110.

Abstract

The human sensor of double-stranded RNA (dsRNA) oligoadenylate synthetase 1 (hOAS1) polymerizes ATP into 2',5'-linked iso-RNA (2-5A) involved in innate immunity, cell cycle, and differentiation. We report the crystal structure of hOAS1 in complex with dsRNA and 2'-deoxy ATP at 2.7 Å resolution, which reveals the mechanism of cytoplasmic dsRNA recognition and activation of oligoadenylate synthetases. Human OAS1 recognizes dsRNA using a previously uncharacterized protein/RNA interface that forms via a conformational change induced by binding of dsRNA. The protein/RNA interface involves two minor grooves and has no sequence-specific contacts, with the exception of a single hydrogen bond between the -NH(2) group of nucleobase G17 and the carbonyl oxygen of serine 56. Using a biochemical readout, we show that hOAS1 undergoes more than 20,000-fold activation upon dsRNA binding and that canonical or GU-wobble substitutions produce dsRNA mutants that retain either full or partial activity, in agreement with the crystal structure. Ultimately, the binding of dsRNA promotes an elaborate conformational rearrangement in the N-terminal lobe of hOAS1, which brings residues D75, D77, and D148 into proximity and creates coordination geometry for binding of two catalytic Mg(2+) ions and ATP. The assembly of this critical active-site structure provides the gate that couples binding of dsRNA to the production and downstream functions of 2-5A.