A cocrystal structure of dengue capsid protein in complex of inhibitor

Xia, Hongjie; Xie, Xuping; Zou, Jing; Noble, Christian G.; Russell, William K.; Holthauzen, Luis Marcelo F.; Choi, Kyung H.; White, Mark A.; Shi, Pei-Yong

doi:10.1073/pnas.2003056117

Title: A cocrystal structure of dengue capsid protein in complex of inhibitor

Journal Article · Wed Jul 15 00:00:00 EDT 2020 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.2003056117· OSTI ID:1657594

^[1]; Xie, Xuping ^[1];

^[1]; Noble, Christian G. ^[2]; Russell, William K. ^[1];

^[1]; Choi, Kyung H. ^[1];

^[1]; Shi, Pei-Yong ^[1]

Univ. of Texas Medical Branch, Galveston, TX (United States)
Syngenta, Berkshire (United Kingdom)

Dengue virus (DENV) was listed 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 Å) 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’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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor; National Institutes of Health (NIH); Sealy & Smith Foundation; Kleberg Foundation; John S. Dunn Foundation; Amon G. Carter Foundation; Gillson Longenbaugh Foundation; Summerfield Robert Foundation; Centers for Disease Control and Prevention (CDC)

Grant/Contract Number:: AC02-06CH11357; 085P1000817; AI142759; AI134907; AI145617; UL1 TR001439; AI087856; AI137627

OSTI ID:: 1657594

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, Issue 30; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 11 works

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Title: A cocrystal structure of dengue capsid protein in complex of inhibitor

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