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Structure of the human metapneumovirus polymerase phosphoprotein complex

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Abstract

Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) cause severe respiratory diseases in infants and elder adults1. Neither a vaccine nor an effective antiviral therapy exists to control RSV or HMPV infections. During viral genome replication and transcription, the tetrameric phosphoprotein P serves as a crucial adaptor between the nucleoprotein-RNA (N-RNA) template and the L protein, which has RNA-dependent RNA polymerase (RdRp), GDP polyribonucleotidyltransferase (PRNTase) and cap-specific methyltransferases (MTases) activities2,3. How P interacts with L and mediates association with the free form of N and with the ribonucleoprotein (RNP) is not clear for HMPV or other prominent human pathogens including measles, Ebola and rabies viruses. Here, we report a cryo-EM reconstruction showing the ring-shaped structure of the polymerase and capping domains of HMPV L, bound with a tetramer of P. The connector and MTase domains are mobile with respect to the core. The putative priming loop important for initiation of RNA synthesis is fully retracted, leaving space in the active-site cavity for RNA elongation. P interacts extensively with the N-terminal region of L, burying more than 4,016 Å2 of molecular surface area in the interface. Two of the four helices forming the coiled-coil tetramerization domain of P, and long C-terminal extensions projecting from these two helices, wrap around the L protein like tentacles. The structural versatility of the four P protomers, which are largely disordered in their free state, demonstrates an example of a “folding-upon-partner-binding” mechanism for carrying-out P adaptor functions. The structure shows that P has the potential to modulate multiple functions of L and should accelerate the design of specific antiviral drugs.

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Author information

Correspondence to Junhua Pan or Rachel Fearns or Julien Lescar.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-2.

Reporting Summary

Video 1:

Overall view of the HMPV L:P complex. Overall structure and organization of the L:P complex. L:P is presented as coloured ribbons and then as coloured molecular surfaces, with the NTD in grey, the RdRp domain in cyan and the capping domain in green. This is followed by L being represented as a molecular surface coloured by electrostatic potential (blue: positive; red: negative). The phosphoprotein asymmetric tetramer comprised of subunits P1, P2, P3 and P4 are represented as coloured ribbons: P1 in magenta, P2: hotpink, P3: salmon and P4: pink. The entry tunnel for rNTPs, exit site of nascent RNA as well as the entry and exit tunnel for the RNA template are indicated.

Video 2:

Close-up views of residues of P interacting with L. L is represented by its molecular surface colored in cyan. P is represented as colored ribbons: in magenta for P1, hotpink for P2, salmon for P3 and pink for P4. The N terminal and C terminal termini of each phosphoprotein subunit are shown. The residues in contacts between P1 and L are displayed and represented as sticks.

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Pan, J., Qian, X., Lattmann, S. et al. Structure of the human metapneumovirus polymerase phosphoprotein complex. Nature (2019) doi:10.1038/s41586-019-1759-1

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