MDA5 (melanoma-differentiation-associated gene 5, also known as IFIH1), as well as RIG-I (Retinoic acid Inducible Gene I, also known as DDX58) and LPG2 (also known as DHX58), contain two N-terminal CARD domains and a C-terminal SF2 helicase domain. They are cytoplasmic DEAD box RNA helicases acting as key innate immune pattern-recognition receptor (PRRs) that play an important role in host antiviral response by sensing incoming viral RNA. Their SF2 helicase domain is comprised of 3 structural domains, the 2 generally conserved helicase domains and a helical domain inserted between the two domains. The inserted domain is involved in conformational changes upon ligand binding.