This entry represents TBK1 inhibitor DP96R from African swine fever virus. DP96R is involved in virus immune evasion through the inhibition of the phosphorylation of the host proteins TBK1 and IKKB [].
This is a coiled-coil domain found in TANK-binding kinase 1 (TBK1), it comprises one of two coiled-coil domains found in the scaffold dimerization region. TBK1 is a serine/threonine kinase and a noncanonical member of the IKK family implicated in diverse cellular functions, including innate immune response as well as tumorigenesis and development []. Deletion of the coiled-coil 1 region in TBK1 lead to a severe impairment in TBK1 function even upon over-expression [].
This is the ubiquitin-like domain (ULD) found in TANK-binding kinase 1 (TBK1). TBK1 is a serine/threonine kinase and a noncanonical member of the IKK family implicated in diverse cellular functions, including innate immune response as well as tumorigenesis and development []. It has been reported that the ULD of TBK1 regulates kinase activity, playing an important role in signaling and mediating interactions with other molecules in the IFN pathway. Deletion of ULD indicates that it is required for the kinase domain to form an enzymatically active conformation. TBK1 ULD has a ubiquitin-like structure and an Ile44 hydrophobic patch, which is conserved among ULDs and IKK and IKK-related proteins. This hydrophobic patch is involved in ULD-SDD interactions in TBK1 and other IKK and IKK-related proteins [].
Suppressor of IKBKE 1 (SIKE) is a physiological suppressor of IKK-epsilon and TBK1 []. IKKepsilon and TBK1 are two IKK-related kinases critically involved in virus- and TLR3-triggered activation of interferon regulatory factor 3 (IRF-3).Other members of this family are circulating cathodic antigen (CCA), found in Schistosoma mansoni (Blood fluke) [, ], and FGFR1 oncogene partner 2, which may be involved in wound healing pathway [].
TANK-binding kinase 1 (TBK1) and inducible IkappaB-kinase (IKK) are central regulators of type-I interferon induction. TANK (TRAF family member-associated NF-kappa-B activator) is aadaptor protein that connects IKK complexes with IKK epsilon and TBK1 kinases [, ]. It negatively regulates NF-kappaB activation by DNA damage via inhibiting ubiquitination of TRAF6 []. It is also a negative regulator of osteoclastogenesis and bone formation [].
Helicase nonstructural protein 13 (NSP13) is encoded by the replicase polyprotein 1a/ab of coronaviruses and released after a proteolytic process. It plays a vital role in catalysing the unwinding of duplex oligonucleotides into single strands in an NTP-dependent manner. It is a multidomain protein which includes an N-terminal Cys/His rich zinc-binding domain (ZBD), followed by a stalk and 1B domains, and a helicase core that belongs to the superfamily SF1 of helicases, containing two RecA1 and RecA2 domains [, ]. The stalk region connects the ZBD domain and 1B domain. Nsp13 adopts a triangular pyramid shape in which the two RecA1 and A2 and 1B domain form the triangular base, while N-terminal ZBD and stalk domains are arranged at the apex of the pyramid [, , ]. Recently, it has been reported that SARS-CoV-2 NSP13 as an interferon antagonist. It is involved in type I interferon (IFN-I) response as it binds and blocks TBK1 phosphorylation to inhibit interferon regulatory factor 3 (IRF3) which results in decreased IRF3 activation [, ].This entry represents the 1B domain, which has a regulatory role modulating the nucleic acid substrate binding. Based on the structures from the related Equine arteritis virus (EAV) NSP10, it is likely that 1B domain forms a channel together with 1A and 2A domains that accommodates the single stranded nucleic acids [, ].
