Limits...
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.


Related in: MedlinePlus

Measles virus (MeV) nucleocapsid architecture. (A) The nucleocapsid (N) protein is composed of an organized domain (Ncore) comprising the NTD arm (light blue, residues 1–36), NTD (blue, 37–265), CTD (tan, 266–371) CTD arm (salmon, 372–391), and a mainly disordered domain (Ntail) comprising three short conserved boxes with the α-MoRE (yellow, 488–499) located in box 2; (B) Surface representation of a cryo-EM reconstruction of the helical MeV nucleocapsid (PDB code 4UFT) [41]. Color coding as in (A), the RNA strand is shown in green; (C) Ribbon representation of two protomers of MeV Ncore (1–391). Color coding as in (A), the adjacent Ni + 1 protomer is shown in grey with the CTD arm colored in black. Left: view from the center of the helical structure. Right: top-down view.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5035965&req=5

viruses-08-00251-f002: Measles virus (MeV) nucleocapsid architecture. (A) The nucleocapsid (N) protein is composed of an organized domain (Ncore) comprising the NTD arm (light blue, residues 1–36), NTD (blue, 37–265), CTD (tan, 266–371) CTD arm (salmon, 372–391), and a mainly disordered domain (Ntail) comprising three short conserved boxes with the α-MoRE (yellow, 488–499) located in box 2; (B) Surface representation of a cryo-EM reconstruction of the helical MeV nucleocapsid (PDB code 4UFT) [41]. Color coding as in (A), the RNA strand is shown in green; (C) Ribbon representation of two protomers of MeV Ncore (1–391). Color coding as in (A), the adjacent Ni + 1 protomer is shown in grey with the CTD arm colored in black. Left: view from the center of the helical structure. Right: top-down view.

Mentions: Morbillivirus N proteins have an approximate length of 525 amino acids, and are mostly well sequence-conserved within the genus. Specifically, sequence alignments among different morbilliviruses have highlighted the existence of a conserved and ordered N-terminal core domain (Ncore) (spanning residues 1–391) that is followed by a far less conserved and intrinsically disordered N-terminal tail domain (Ntail) domain (residues 392–525) [30,36] (Figure 2A). Trypsin digestion of recombinant nucleocapsids has demonstrated resistance of Ncores to proteolysis. However, Ntails were sensitive to trypsin proteolysis, resulting in the conversion of nucleocapsids into rigid herringbone-like structures with a diameter of approximately 20 nm and a shortened pitch of 5 nm, compared to approximately 6.4 nm measured for native nucleocapsids that were found in infected cells [37,38,39]. Native MeV genomes present in viral particles have been reconstructed by cryo-electron microscopy, and show a flexible left handed herringbone structure similar to that described previously for recombinant nucleocapsid. However, structures of a larger diameter (30 nm) were also found that were coated by an additional layer of the viral M protein [40]. The physiological significance and/or functional importance of these matrix-wrapped structures is untested at present.


Organization, Function, and Therapeutic Targeting of the Morbillivirus RNA-Dependent RNA Polymerase Complex
Measles virus (MeV) nucleocapsid architecture. (A) The nucleocapsid (N) protein is composed of an organized domain (Ncore) comprising the NTD arm (light blue, residues 1–36), NTD (blue, 37–265), CTD (tan, 266–371) CTD arm (salmon, 372–391), and a mainly disordered domain (Ntail) comprising three short conserved boxes with the α-MoRE (yellow, 488–499) located in box 2; (B) Surface representation of a cryo-EM reconstruction of the helical MeV nucleocapsid (PDB code 4UFT) [41]. Color coding as in (A), the RNA strand is shown in green; (C) Ribbon representation of two protomers of MeV Ncore (1–391). Color coding as in (A), the adjacent Ni + 1 protomer is shown in grey with the CTD arm colored in black. Left: view from the center of the helical structure. Right: top-down view.
© Copyright Policy
Related In: Results  -  Collection

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

viruses-08-00251-f002: Measles virus (MeV) nucleocapsid architecture. (A) The nucleocapsid (N) protein is composed of an organized domain (Ncore) comprising the NTD arm (light blue, residues 1–36), NTD (blue, 37–265), CTD (tan, 266–371) CTD arm (salmon, 372–391), and a mainly disordered domain (Ntail) comprising three short conserved boxes with the α-MoRE (yellow, 488–499) located in box 2; (B) Surface representation of a cryo-EM reconstruction of the helical MeV nucleocapsid (PDB code 4UFT) [41]. Color coding as in (A), the RNA strand is shown in green; (C) Ribbon representation of two protomers of MeV Ncore (1–391). Color coding as in (A), the adjacent Ni + 1 protomer is shown in grey with the CTD arm colored in black. Left: view from the center of the helical structure. Right: top-down view.
Mentions: Morbillivirus N proteins have an approximate length of 525 amino acids, and are mostly well sequence-conserved within the genus. Specifically, sequence alignments among different morbilliviruses have highlighted the existence of a conserved and ordered N-terminal core domain (Ncore) (spanning residues 1–391) that is followed by a far less conserved and intrinsically disordered N-terminal tail domain (Ntail) domain (residues 392–525) [30,36] (Figure 2A). Trypsin digestion of recombinant nucleocapsids has demonstrated resistance of Ncores to proteolysis. However, Ntails were sensitive to trypsin proteolysis, resulting in the conversion of nucleocapsids into rigid herringbone-like structures with a diameter of approximately 20 nm and a shortened pitch of 5 nm, compared to approximately 6.4 nm measured for native nucleocapsids that were found in infected cells [37,38,39]. Native MeV genomes present in viral particles have been reconstructed by cryo-electron microscopy, and show a flexible left handed herringbone structure similar to that described previously for recombinant nucleocapsid. However, structures of a larger diameter (30 nm) were also found that were coated by an additional layer of the viral M protein [40]. The physiological significance and/or functional importance of these matrix-wrapped structures is untested at present.

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.


Related in: MedlinePlus