Structures of the prefusion form of measles virus fusion protein in complex with inhibitors

Takao Hashiguchi, Yoshinari Fukuda, Rei Matsuoka, Daisuke Kuroda, Marie Kubota, Yuta Shirogane, Shumpei Watanabe, Kouhei Tsumoto, Daisuke Kohda, Richard Karl Plemper, Yusuke Yanagi

研究成果: ジャーナルへの寄稿記事

7 引用 (Scopus)

抄録

Measles virus (MeV), a major cause of childhood morbidity and mortality, is highly immunotropic and one of the most contagious pathogens. MeV may establish, albeit rarely, persistent infection in the central nervous system, causing fatal and intractable neurodegenerative diseases such as subacute sclerosing panencephalitis and measles inclusion body encephalitis. Recent studies have suggested that particular substitutions in the MeV fusion (F) protein are involved in the pathogenesis by destabilizing the F protein and endowing it with hyperfusogenicity. Here we show the crystal structures of the prefusion MeV-F alone and in complex with the small compound AS-48 or a fusion inhibitor peptide. Notably, these independently developed inhibitors bind the same hydrophobic pocket located at the region connecting the head and stalk of MeV-F, where a number of substitutions in MeV isolates from neurodegenerative diseases are also localized. Since these inhibitors could suppress membrane fusion mediated by most of the hyperfusogenic MeV-F mutants, the development of more effective inhibitors based on the structures may be warranted to treat MeV-induced neurodegenerative diseases.

元の言語英語
ページ(範囲)2496-2501
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
115
発行部数10
DOI
出版物ステータス出版済み - 3 6 2018

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Viral Fusion Proteins
Measles virus
Neurodegenerative Diseases
Subacute Sclerosing Panencephalitis
Central Nervous System Infections
Membrane Fusion
Head
Morbidity
Peptides
Mortality

All Science Journal Classification (ASJC) codes

  • General

これを引用

Structures of the prefusion form of measles virus fusion protein in complex with inhibitors. / Hashiguchi, Takao; Fukuda, Yoshinari; Matsuoka, Rei; Kuroda, Daisuke; Kubota, Marie; Shirogane, Yuta; Watanabe, Shumpei; Tsumoto, Kouhei; Kohda, Daisuke; Plemper, Richard Karl; Yanagi, Yusuke.

:: Proceedings of the National Academy of Sciences of the United States of America, 巻 115, 番号 10, 06.03.2018, p. 2496-2501.

研究成果: ジャーナルへの寄稿記事

Hashiguchi, Takao ; Fukuda, Yoshinari ; Matsuoka, Rei ; Kuroda, Daisuke ; Kubota, Marie ; Shirogane, Yuta ; Watanabe, Shumpei ; Tsumoto, Kouhei ; Kohda, Daisuke ; Plemper, Richard Karl ; Yanagi, Yusuke. / Structures of the prefusion form of measles virus fusion protein in complex with inhibitors. :: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; 巻 115, 番号 10. pp. 2496-2501.
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abstract = "Measles virus (MeV), a major cause of childhood morbidity and mortality, is highly immunotropic and one of the most contagious pathogens. MeV may establish, albeit rarely, persistent infection in the central nervous system, causing fatal and intractable neurodegenerative diseases such as subacute sclerosing panencephalitis and measles inclusion body encephalitis. Recent studies have suggested that particular substitutions in the MeV fusion (F) protein are involved in the pathogenesis by destabilizing the F protein and endowing it with hyperfusogenicity. Here we show the crystal structures of the prefusion MeV-F alone and in complex with the small compound AS-48 or a fusion inhibitor peptide. Notably, these independently developed inhibitors bind the same hydrophobic pocket located at the region connecting the head and stalk of MeV-F, where a number of substitutions in MeV isolates from neurodegenerative diseases are also localized. Since these inhibitors could suppress membrane fusion mediated by most of the hyperfusogenic MeV-F mutants, the development of more effective inhibitors based on the structures may be warranted to treat MeV-induced neurodegenerative diseases.",
author = "Takao Hashiguchi and Yoshinari Fukuda and Rei Matsuoka and Daisuke Kuroda and Marie Kubota and Yuta Shirogane and Shumpei Watanabe and Kouhei Tsumoto and Daisuke Kohda and Plemper, {Richard Karl} and Yusuke Yanagi",
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AU - Hashiguchi, Takao

AU - Fukuda, Yoshinari

AU - Matsuoka, Rei

AU - Kuroda, Daisuke

AU - Kubota, Marie

AU - Shirogane, Yuta

AU - Watanabe, Shumpei

AU - Tsumoto, Kouhei

AU - Kohda, Daisuke

AU - Plemper, Richard Karl

AU - Yanagi, Yusuke

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N2 - Measles virus (MeV), a major cause of childhood morbidity and mortality, is highly immunotropic and one of the most contagious pathogens. MeV may establish, albeit rarely, persistent infection in the central nervous system, causing fatal and intractable neurodegenerative diseases such as subacute sclerosing panencephalitis and measles inclusion body encephalitis. Recent studies have suggested that particular substitutions in the MeV fusion (F) protein are involved in the pathogenesis by destabilizing the F protein and endowing it with hyperfusogenicity. Here we show the crystal structures of the prefusion MeV-F alone and in complex with the small compound AS-48 or a fusion inhibitor peptide. Notably, these independently developed inhibitors bind the same hydrophobic pocket located at the region connecting the head and stalk of MeV-F, where a number of substitutions in MeV isolates from neurodegenerative diseases are also localized. Since these inhibitors could suppress membrane fusion mediated by most of the hyperfusogenic MeV-F mutants, the development of more effective inhibitors based on the structures may be warranted to treat MeV-induced neurodegenerative diseases.

AB - Measles virus (MeV), a major cause of childhood morbidity and mortality, is highly immunotropic and one of the most contagious pathogens. MeV may establish, albeit rarely, persistent infection in the central nervous system, causing fatal and intractable neurodegenerative diseases such as subacute sclerosing panencephalitis and measles inclusion body encephalitis. Recent studies have suggested that particular substitutions in the MeV fusion (F) protein are involved in the pathogenesis by destabilizing the F protein and endowing it with hyperfusogenicity. Here we show the crystal structures of the prefusion MeV-F alone and in complex with the small compound AS-48 or a fusion inhibitor peptide. Notably, these independently developed inhibitors bind the same hydrophobic pocket located at the region connecting the head and stalk of MeV-F, where a number of substitutions in MeV isolates from neurodegenerative diseases are also localized. Since these inhibitors could suppress membrane fusion mediated by most of the hyperfusogenic MeV-F mutants, the development of more effective inhibitors based on the structures may be warranted to treat MeV-induced neurodegenerative diseases.

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