@article{f942637ed5444fdbb0a063181aa7fde1,
title = "A cocrystal structure of dengue capsid protein in complex of inhibitor",
abstract = "Dengue virus (DENV) was designated as a top 10 public health threat by the World Health Organization in 2019. No clinically approved anti-DENV drug is currently available. Here we report the high-resolution cocrystal structure (1.5 {\AA}) of the DENV-2 capsid protein in complex with an inhibitor that potently suppresses DENV-2 but not other DENV serotypes. The inhibitor induces a “kissing” interaction between two capsid dimers. The inhibitor-bound capsid tetramers are assembled inside virions, resulting in defective uncoating of nucleocapsid when infecting new cells. Resistant DENV-2 emerges through one mutation that abolishes hydrogen bonds in the capsid structure, leading to a loss of compound binding. Structure-based analysis has defined the amino acids responsible for the inhibitor{\textquoteright}s inefficacy against other DENV serotypes. The results have uncovered an antiviral mechanism through inhibitor-induced tetramerization of the viral capsid and provided essential structural and functional knowledge for rational design of panserotype DENV capsid inhibitors.",
keywords = "Antiviral drug, Capsid, Dengue, Flavivirus, Virus assembly",
author = "Hongjie Xia and Xuping Xie and Jing Zou and Noble, {Christian G.} and Russell, {William K.} and Holthauzen, {Luis Marcelo F.} and Choi, {Kyung H.} and White, {Mark A.} and Shi, {Pei Yong}",
note = "Funding Information: the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817). P.-Y.S. was supported by NIH Grants AI142759, AI134907, and AI145617 and Clinical and Translational Science Award UL1 TR001439; awards from the Sealy & Smith Foundation, Kleberg Foundation, John S. Dunn Foundation, Amon G. Carter Foundation, Gillson Longenbaugh Foundation, and Summerfield Robert Foundation; and CDC Cooperative Agreement U01CK000512. K.H.C. is supported by NIH Grants AI087856 and AI137627. We also thank Jianmei Wang at the UTMB Mass Spectrometry Facility for technical support. Funding Information: We thank the Sealy Center for Structural Biology and Molecular Biophysics at the University of Texas Medical Branch (UTMB) at Galveston for providing research resources. This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817). P.-Y.S. was supported by NIH Grants AI142759, AI134907, and AI145617 and Clinical and Translational Science Award UL1 TR001439; awards from the Sealy & Smith Foundation, Kleberg Foundation, John S. Dunn Foundation, Amon G. Carter Foundation, Gillson Longenbaugh Foundation, and Summerfield Robert Foundation; and CDC Cooperative Agreement U01CK000512. K.H.C. is supported by NIH Grants AI087856 and AI137627. We also thank Jianmei Wang at the UTMB Mass Spectrometry Facility for technical support. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = jul,
day = "28",
doi = "10.1073/pnas.2003056117",
language = "English (US)",
volume = "117",
pages = "17992--18001",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "30",
}