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Nature. 2019 Nov 7. doi: 10.1038/s41586-019-1759-1. [Epub ahead of print]

Structure of the human metapneumovirus polymerase phosphoprotein complex.

Author information

1
Division of Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. pan@crystal.harvard.edu.
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. pan@crystal.harvard.edu.
3
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
4
NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore.
5
Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore.
6
Boston University School of Medicine, National Emerging Infectious Diseases Laboratories, Boston, MA, USA.
7
Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
8
Boston University School of Medicine, National Emerging Infectious Diseases Laboratories, Boston, MA, USA. rfearns@bu.edu.
9
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore. julien@ntu.edu.sg.
10
NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore. julien@ntu.edu.sg.
11
Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology, Singapore, Singapore. julien@ntu.edu.sg.

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.

PMID:
31698413
DOI:
10.1038/s41586-019-1759-1

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