Structure of the human metapneumovirus polymerase phosphoprotein complex

Pan, Junhua; Qian, Xinlei; Lattmann, Simon; Sahili, Abbas El; Yeo, Tiong Han; Jia, Hongyan; Cressey, Tessa N.; Lüdeke, Barbara; Noton, Sarah L.; Kalocsay, Marian; Fearns, Rachel; Lescar, Julien

doi:10.1038/s41586-019-1759-1

Cited by 83 publications

(150 citation statements)

References 47 publications

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“…Priming, Initiation, Elongation, and Capping. The structure described here, together with those of VSV L-P at 3.0 Å resolution (7) and of two recently published pneumovirus L-P complexes (5,6), suggests a mechanism for switching between replication and transcription, with alternative priming configurations and alternative sites for product exit.…”

Section: Resultsmentioning

confidence: 56%

“…Elongation beyond formation of the initial dinucleotide requires that the priming loop retract into the CAP catalytic cavity. The recent pneumovirus L-P structures show just such a retracted configuration (5,6). A nascent transcript can then pass across the retracted loop.…”

Section: Resultsmentioning

confidence: 99%

“…This closed conformation appears to represent the L protein poised for initiation at the 3′ end of the genome or antigenome. Comparison with structures of two recently published pneumovirus L-P complexes (5,6) as well as with that of a VSV L-P reconstruction determined at 3.0 Å resolution (7) suggests that replication and transcription have alternative priming configurations and alternative product exit sites.…”

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confidence: 86%

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Structure of a rabies virus polymerase complex from electron cryo-microscopy

Horwitz

Jenni

Harrison

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Nonsegmented negative-stranded (NNS) RNA viruses, among them the virus that causes rabies (RABV), include many deadly human pathogens. The large polymerase (L) proteins of NNS RNA viruses carry all of the enzymatic functions required for viral messenger RNA (mRNA) transcription and replication: RNA polymerization, mRNA capping, and cap methylation. We describe here a complete structure of RABV L bound with its phosphoprotein cofactor (P), determined by electron cryo-microscopy at 3.3 Å resolution. The complex closely resembles the vesicular stomatitis virus (VSV) L-P, the one other known full-length NNS-RNA L-protein structure, with key local differences (e.g., in L-P interactions). Like the VSV L-P structure, the RABV complex analyzed here represents a preinitiation conformation. Comparison with the likely elongation state, seen in two structures of pneumovirus L-P complexes, suggests differences between priming/initiation and elongation complexes. Analysis of internal cavities within RABV L suggests distinct template and product entry and exit pathways during transcription and replication. rabies lyssavirus | NNS RNA viruses | vesicular stomatitis virus | transcription | replication

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Section: Resultsmentioning

confidence: 56%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 86%

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Structure of a rabies virus polymerase complex from electron cryo-microscopy

Horwitz

Jenni

Harrison

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Reflecting major efforts to identify a cost-effective alternative to high-price passive immunization with anti-RSV nAbs, a number of compounds have entered advanced preclinical development and clinical testing in recent years (Table 1). Breakthroughs in the structural and functional characterization of the viral entry machinery and polymerase complexes in the past decade [12][13][14][15][16][17][18][19][20][21] have furthermore created a novel opportunity for structure-informed mechanistic characterization and ligand optimization.…”

mentioning

confidence: 99%

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

Aggarwal

Plemper

2020

Viruses

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Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV), measles virus (MeV), human parainfluenza viruses (HPIVs), and highly pathogenic Nipah virus (NiV). High-resolution F protein structures in both the metastable pre-and the postfusion conformation have been solved for several members of the families and a number of F-targeting entry inhibitors have progressed to advanced development or clinical testing. However, small-molecule RSV entry inhibitors have overall disappointed in clinical trials and viral resistance developed rapidly in experimental settings and patients, raising the question of whether the available structural information may provide a path to counteract viral escape through proactive inhibitor engineering. This article will summarize current mechanistic insight into F-mediated membrane fusion and examine the contribution of structural information to the development of small-molecule F inhibitors. Implications are outlined for future drug target selection and rational drug engineering strategies.Viruses 2020, 12, 342 2 of 16 from its natural bat host to domestic animals, resulting in case/fatality rates reaching from 40% to over 90% [9]. Continued spillover into the human population must be expected, and human-to-human transmission through respiratory secretions, urine, and saliva has been documented [10].Of the pneumoviruses, RSV infects almost all children before two years of age and is responsible for over 100,000 hospitalizations yearly in the United States alone. The monoclonal antibody palivizumab has been approved for immunoprophylaxis against RSV infection [11], however, use is restricted to high-risk patients due to the high-cost and need for prophylactic administration.Given the health, medical and economic burden associated with paramyxo-and pneumovirus infections, a major and currently unmet clinical need exists to expedite the development of novel safe and effective therapeutics for improved disease management and outbreak control. Current direct-acting therapeutics predominantly focus on preventing viral entry through neutralizing antibodies (nAbs) and on small-molecules targeting the envelope glycoproteins or inhibiting the viral RNA-dependent RNA polymerase (RdRP) complex. Reflecting major efforts to identify a cost-effective alternative to high-price passive immunization with anti-RSV nAbs, a number of compounds have entered advanced preclinical development and clinical testing in recent years (Table 1). Breakthroughs in the structural and functional characterization of the viral entry machinery and polymerase complexes in the past decade [12][13][14][15][16][17][18][19][20][21] have furthermore created a novel opportunity for structure-informed mechanistic characterization and ligand optimization.

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“…To increase the number of treatment options, methods are now being developed to expedite the screening of anti-HMPV drug candidates [56]. Ongoing studies of HMPV protein structure/function will also assist future drug and vaccine development [57,58].…”

Section: Treatment and Drug Discovery Effortsmentioning

confidence: 99%

Human Metapneumovirus: A Largely Unrecognized Threat to Human Health

et al. 2020

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Human metapneumovirus (HMPV) infects most children by five years of age. The virus can cause both upper and lower respiratory tract disease and can be life threatening. High-risk populations include young children who are exposed to virus for the first time and the elderly. Currently, there is no standard treatment nor licensed vaccine for HMPV, although several attractive vaccine candidates have been developed for pre-clinical studies. A raised awareness of the impact of HMPV on public health is needed to drive research, complete vaccine development, and thereby prevent significant virus-associated morbidities and mortalities worldwide.

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Structure of the human metapneumovirus polymerase phosphoprotein complex

Cited by 83 publications

References 47 publications

Structure of a rabies virus polymerase complex from electron cryo-microscopy

Structure of a rabies virus polymerase complex from electron cryo-microscopy

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

Human Metapneumovirus: A Largely Unrecognized Threat to Human Health

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