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Organization, Function, and Therapeutic Targeting of the Morbillivirus RNA-Dependent RNA Polymerase Complex

View Article: PubMed Central - PubMed

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.

No MeSH data available.


MeV N0-P interactions. (A) Ribbon representation of the crystal structure of a monomer of MeV N (residues 21–425) in complex with P (residues 1–48) (PDB code 5E4V) [42]. (B) Ribbon representation of the crystal structure of an MeV nucleocapsid protomer [41]. Both structures are oriented using the first CTD alpha helix as a reference. Color coding: NTD in blue, CTD in salmon, P residues 1–48 in orange, RNA is shown in green. Adjacent interacting NT- and CT-arms are rendered in grey.
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viruses-08-00251-f003: MeV N0-P interactions. (A) Ribbon representation of the crystal structure of a monomer of MeV N (residues 21–425) in complex with P (residues 1–48) (PDB code 5E4V) [42]. (B) Ribbon representation of the crystal structure of an MeV nucleocapsid protomer [41]. Both structures are oriented using the first CTD alpha helix as a reference. Color coding: NTD in blue, CTD in salmon, P residues 1–48 in orange, RNA is shown in green. Adjacent interacting NT- and CT-arms are rendered in grey.

Mentions: Whereas the N protein has a strong tendency to oligomerize and bind RNA, it is imperative that a sufficiently large pool of monomeric, RNA-free N (N0) proteins can be accumulated in infected cells before the viral RdRp commits to replicase mode, to ensure uninterrupted cotranscriptional encapsidation of viral RNA. A recently solved X-ray structure of a chimeric protein of the MeV Ncore fragment (21–408) fused to the N-terminal fragment of the P protein (1–48) provided first insight into the organization of N0, facilitating a direct comparison of an RNA-bound and RNA-free morbillivirus N protein [42]. This structure revealed a direct interaction of P protein residues 1–48 with Ncore, specifically with the first alpha helix present in the N-CTD (Figure 3). Moreover, structure comparison with an N protomer embedded in assembled nucleocapsids shows that the position of P protein residues 1–48 in P-N0 complexes overlaps with that of the N-i NT-arm and Ni + 1 CT-arm in the helical assembly, conceivably sterically impeding the polymerization of P bound N proteins.


Organization, Function, and Therapeutic Targeting of the Morbillivirus RNA-Dependent RNA Polymerase Complex
MeV N0-P interactions. (A) Ribbon representation of the crystal structure of a monomer of MeV N (residues 21–425) in complex with P (residues 1–48) (PDB code 5E4V) [42]. (B) Ribbon representation of the crystal structure of an MeV nucleocapsid protomer [41]. Both structures are oriented using the first CTD alpha helix as a reference. Color coding: NTD in blue, CTD in salmon, P residues 1–48 in orange, RNA is shown in green. Adjacent interacting NT- and CT-arms are rendered in grey.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5035965&req=5

viruses-08-00251-f003: MeV N0-P interactions. (A) Ribbon representation of the crystal structure of a monomer of MeV N (residues 21–425) in complex with P (residues 1–48) (PDB code 5E4V) [42]. (B) Ribbon representation of the crystal structure of an MeV nucleocapsid protomer [41]. Both structures are oriented using the first CTD alpha helix as a reference. Color coding: NTD in blue, CTD in salmon, P residues 1–48 in orange, RNA is shown in green. Adjacent interacting NT- and CT-arms are rendered in grey.
Mentions: Whereas the N protein has a strong tendency to oligomerize and bind RNA, it is imperative that a sufficiently large pool of monomeric, RNA-free N (N0) proteins can be accumulated in infected cells before the viral RdRp commits to replicase mode, to ensure uninterrupted cotranscriptional encapsidation of viral RNA. A recently solved X-ray structure of a chimeric protein of the MeV Ncore fragment (21–408) fused to the N-terminal fragment of the P protein (1–48) provided first insight into the organization of N0, facilitating a direct comparison of an RNA-bound and RNA-free morbillivirus N protein [42]. This structure revealed a direct interaction of P protein residues 1–48 with Ncore, specifically with the first alpha helix present in the N-CTD (Figure 3). Moreover, structure comparison with an N protomer embedded in assembled nucleocapsids shows that the position of P protein residues 1–48 in P-N0 complexes overlaps with that of the N-i NT-arm and Ni + 1 CT-arm in the helical assembly, conceivably sterically impeding the polymerization of P bound N proteins.

View Article: PubMed Central - PubMed

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.

No MeSH data available.