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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 P protein architecture. (A) Domain organization of the P protein. PMD: multimerization domain (residues 304–376) [56]; NBD: N0 binding domain (residues 1–48), including a soyuz1 motif [42,65]; PXD: N-tail binding domain (residues 459–507) [66]; (B) Ribbon representation of a PMD crystal structure (PDB code 3ZDO) [56]; (C) Ribbon representation of P-XD crystal structure (PDB code 1 OKS) [66].
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viruses-08-00251-f005: MeV P protein architecture. (A) Domain organization of the P protein. PMD: multimerization domain (residues 304–376) [56]; NBD: N0 binding domain (residues 1–48), including a soyuz1 motif [42,65]; PXD: N-tail binding domain (residues 459–507) [66]; (B) Ribbon representation of a PMD crystal structure (PDB code 3ZDO) [56]; (C) Ribbon representation of P-XD crystal structure (PDB code 1 OKS) [66].

Mentions: Sequence alignments of morbillivirus P proteins suggested the presence of a coiled-coil oligomerization domain spanning residues 304–369 [55]. This notion was confirmed through crystallization of this region derived from the MeV P protein [56] (Figure 5). The recent structural work on MeV P corroborated earlier work studying RPV P, since sequential deletions of this region spotlighted RPV P residues 316–347 as required for oligomerization in a yeast two-hybrid assay. Furthermore, an RPV P fragment spanning residues 316 to 382 spontaneously tetramerized in solution and was predicted to assemble into a coiled-coil structure [57,58].


Organization, Function, and Therapeutic Targeting of the Morbillivirus RNA-Dependent RNA Polymerase Complex
MeV P protein architecture. (A) Domain organization of the P protein. PMD: multimerization domain (residues 304–376) [56]; NBD: N0 binding domain (residues 1–48), including a soyuz1 motif [42,65]; PXD: N-tail binding domain (residues 459–507) [66]; (B) Ribbon representation of a PMD crystal structure (PDB code 3ZDO) [56]; (C) Ribbon representation of P-XD crystal structure (PDB code 1 OKS) [66].
© Copyright Policy
Related In: Results  -  Collection

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

viruses-08-00251-f005: MeV P protein architecture. (A) Domain organization of the P protein. PMD: multimerization domain (residues 304–376) [56]; NBD: N0 binding domain (residues 1–48), including a soyuz1 motif [42,65]; PXD: N-tail binding domain (residues 459–507) [66]; (B) Ribbon representation of a PMD crystal structure (PDB code 3ZDO) [56]; (C) Ribbon representation of P-XD crystal structure (PDB code 1 OKS) [66].
Mentions: Sequence alignments of morbillivirus P proteins suggested the presence of a coiled-coil oligomerization domain spanning residues 304–369 [55]. This notion was confirmed through crystallization of this region derived from the MeV P protein [56] (Figure 5). The recent structural work on MeV P corroborated earlier work studying RPV P, since sequential deletions of this region spotlighted RPV P residues 316–347 as required for oligomerization in a yeast two-hybrid assay. Furthermore, an RPV P fragment spanning residues 316 to 382 spontaneously tetramerized in solution and was predicted to assemble into a coiled-coil structure [57,58].

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.