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The structural basis of African swine fever virus pA104R binding to DNA and its inhibition by stilbene derivatives.
Liu, Ruili; Sun, Yeping; Chai, Yan; Li, Su; Li, Shihua; Wang, Liang; Su, Jiaqi; Yu, Shaoxiong; Yan, Jinghua; Gao, Feng; Zhang, Gaiping; Qiu, Hua-Ji; Gao, George F; Qi, Jianxun; Wang, Han.
Afiliação
  • Liu R; College of Animal Science and Veterinary Medicine, Henan Agricultural University, 450046 Zhengzhou, Henan, China.
  • Sun Y; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China.
  • Chai Y; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China.
  • Li S; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China.
  • Li S; State Key Laboratory of Veterinary Biotechnology and National High-Containment Laboratory for Animal Diseases Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 150069 Harbin, China.
  • Wang L; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China.
  • Su J; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China.
  • Yu S; Savaid Medical School, University of Chinese Academy of Sciences, 100049 Beijing, China.
  • Yan J; State Key Laboratory of Veterinary Biotechnology and National High-Containment Laboratory for Animal Diseases Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 150069 Harbin, China.
  • Gao F; CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China.
  • Zhang G; Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 300308 Tianjin, China.
  • Qiu HJ; College of Animal Science and Veterinary Medicine, Henan Agricultural University, 450046 Zhengzhou, Henan, China.
  • Gao GF; State Key Laboratory of Veterinary Biotechnology and National High-Containment Laboratory for Animal Diseases Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 150069 Harbin, China.
  • Qi J; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China; gaof@im.ac.cn jxqi@im.ac.cn wanghan@im.ac.cn.
  • Wang H; Savaid Medical School, University of Chinese Academy of Sciences, 100049 Beijing, China.
Proc Natl Acad Sci U S A ; 117(20): 11000-11009, 2020 05 19.
Article em En | MEDLINE | ID: mdl-32358196
African swine fever virus (ASFV) is a highly contagious nucleocytoplasmic large DNA virus (NCLDV) that causes nearly 100% mortality in swine. The development of effective vaccines and drugs against this virus is urgently needed. pA104R, an ASFV-derived histone-like protein, shares sequence and functional similarity with bacterial HU/IHF family members and is essential for viral replication. Herein, we solved the crystal structures of pA104R in its apo state as well as in complex with DNA. Apo-pA104R forms a homodimer and folds into an architecture conserved in bacterial heat-unstable nucleoid proteins/integration host factors (HUs/IHFs). The pA104R-DNA complex structure, however, uncovers that pA104R has a DNA binding pattern distinct from its bacterial homologs, that is, the ß-ribbon arms of pA104R stabilize DNA binding by contacting the major groove instead of the minor groove. Mutations of the basic residues at the base region of the ß-strand DNA binding region (BDR), rather than those in the ß-ribbon arms, completely abolished DNA binding, highlighting the major role of the BDR base in DNA binding. An overall DNA bending angle of 93.8° is observed in crystal packing of the pA104R-DNA complex structure, which is close to the DNA bending angle in the HU-DNA complex. Stilbene derivatives SD1 and SD4 were shown to disrupt the binding between pA104R and DNA and inhibit the replication of ASFV in primary porcine alveolar macrophages. Collectively, these results reveal the structural basis of pA104R binding to DNA highlighting the importance of the pA104R-DNA interaction in the ASFV replication cycle and provide inhibitor leads for ASFV chemotherapy.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Estilbenos / DNA / Vírus da Febre Suína Africana / Proteínas de Ligação a DNA Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2020 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Estilbenos / DNA / Vírus da Febre Suína Africana / Proteínas de Ligação a DNA Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2020 Tipo de documento: Article País de afiliação: China