2015
DOI: 10.1038/ncomms9749
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X-ray structure and activities of an essential Mononegavirales L-protein domain

Abstract: The L protein of mononegaviruses harbours all catalytic activities for genome replication and transcription. It contains six conserved domains (CR-I to -VI; Fig. 1a). CR-III has been linked to polymerase and polyadenylation activity, CR-V to mRNA capping and CR-VI to cap methylation. However, how these activities are choreographed is poorly understood. Here we present the 2.2-Å X-ray structure and activities of CR-VI+, a portion of human Metapneumovirus L consisting of CR-VI and the poorly conserved region at … Show more

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Cited by 57 publications
(84 citation statements)
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“…Thus, the VSV L structure provides a framework for integrating this information and drawing conclusions regarding the structure-function relationships of paramyxo- and pneumovirus polymerases. In addition, the structure of a C-terminal fragment of the HMPV L protein in the presence or absence of substrate has been resolved by X-ray crystallography and analyzed by mutation analysis (26), which provides further information regarding the spatial organization of the methyltransferase and C-terminal domain that helps inform our understanding of the paramyxo- and pneumovirus polymerases.…”
Section: Paramyxo- and Pneumovirus Polymerase Structure And Enzymaticmentioning
confidence: 99%
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“…Thus, the VSV L structure provides a framework for integrating this information and drawing conclusions regarding the structure-function relationships of paramyxo- and pneumovirus polymerases. In addition, the structure of a C-terminal fragment of the HMPV L protein in the presence or absence of substrate has been resolved by X-ray crystallography and analyzed by mutation analysis (26), which provides further information regarding the spatial organization of the methyltransferase and C-terminal domain that helps inform our understanding of the paramyxo- and pneumovirus polymerases.…”
Section: Paramyxo- and Pneumovirus Polymerase Structure And Enzymaticmentioning
confidence: 99%
“…L fragments containing conserved region VI of Sendai virus, rinderpest virus and HMPV are able to methylate RNAs provided in trans (26, 59) (60), and substitutions in conserved region VI of Sendai virus inhibit cap methylation (20, 22, 23). The structure of the C-terminus of the HMPV L protein, containing conserved region VI and the C-terminal domain was recently resolved to 2.2 Angstroms in the presence and absence of S-adenosyl methionine and NTPs, and the enzymatic properties of this region were analyzed using biochemical assays (26). The crystal structure predicted that the C-terminal domain of HMPV L folds over the active site cleft of the methyltransferase domain in conserved region VI and creates a substrate binding pocket that presumably accommodates the nucleotide that is being methylated (Figure 5).…”
Section: Paramyxo- and Pneumovirus Polymerase Structure And Enzymaticmentioning
confidence: 99%
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“…Finally, CR VI contains methyltransferase (MTase) activity [55, 69]. Recently, the structure of the closely related human metapneumovirus (HMPV) L methyltransferase domain was solved [70], which like RSV, belongs to the pneumovirinae subfamily within the paramyxoviruses. This high-resolution structure has strong potential to guide the future design of novel MTase inhibitor candidates.…”
Section: 1 the Rsv Rdrp Complexmentioning
confidence: 99%