Abstract
The morbillivirus genus comprises major human and animal pathogens, including the highly contagious measles virus. Morbilliviruses feature single stranded negative sense RNA genomes that are wrapped by a plasma membrane-derived lipid envelope. Genomes are encapsidated by the viral nucleocapsid protein forming ribonucleoprotein complexes, and only the encapsidated RNA is transcribed and replicated by the viral RNA-dependent RNA polymerase (RdRp). In this review, we discuss recent breakthroughs towards the structural and functional understanding of the morbillivirus polymerase complex. Considering the clinical burden imposed by members of the morbillivirus genus, the development of novel antiviral therapeutics is urgently needed. The viral polymerase complex presents unique structural and enzymatic properties that can serve as attractive candidates for druggable targets. We evaluate distinct strategies for therapeutic intervention and examine how high-resolution insight into the organization of the polymerase complex may pave the path towards the structure-based design and optimization of next-generation RdRp inhibitors.
Highlights
The paramyxovirus family encompasses a broad and diverse range of human and animal pathogens
[33]; and (iii) outside of thehave supported by three lines of evidence: (i) yeast two hybrid studies with RPV RNA Dependent RNA Polymerase (RdRp) components morbillivirus genus, the P interaction domain with L was mapped downstream of the oligomerization demonstrated that the interaction of RPV L with P involves P residues 347 to 490 [68]; (ii) this RPV P
Candidate binding region is able to engage in heterologous complexes between RPV and PPRV [33]; and (iii) outside of the morbillivirus genus, the P interaction domain with L was mapped downstream of the oligomerization domain for polymerase complexes of the human parainfluenza viruses type 2 and 3 and Sendai virus (SeV) [69,70,71]
Summary
The paramyxovirus family encompasses a broad and diverse range of human and animal pathogens. Recognition Element (MoRE), which interacts with an X domain in the P protein (P‐XD) that a dramatic loss in RdRp activity in MeV minireplicon assays [45]. MoRE assumes a molten globule conformation that with a role of Ntail in RdRp recruitment to the nucleocapsid, since box 2 contains a binding site for the transiently folds into short alpha helical structures, which are thought to establish the initial contact with. MeV RdRp complex onto the RNP template must be mediated by a direct interaction between P-L and Ncore in assembled nucleocapsids. The α‐MoRE of N has an alpha helical complex; (B) Ribbon representation of the crystal structure of a chimeric protein comprising PXD conformation spanning residues 487–503 and interacts with the second and third helixes of P‐XD.
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