Hepatitis B Virus Capsids Have Diverse Structural Responses to Small-Molecule Ligands Bound to the Heteroaryldihydropyrimidine Pocket

Venkatakrishnan, Balasubramanian; Katen, Sarah P.; Francis, Samson; Chirapu, Srinivas; Finn, M. G.; Zlotnick, Adam

doi:10.1128/JVI.03058-15

Title: Hepatitis B Virus Capsids Have Diverse Structural Responses to Small-Molecule Ligands Bound to the Heteroaryldihydropyrimidine Pocket

Journal Article · Mon Mar 28 00:00:00 EDT 2016 · Journal of Virology

DOI:https://doi.org/10.1128/JVI.03058-15· OSTI ID:1247336

Venkatakrishnan, Balasubramanian ^[1]; Katen, Sarah P. ^[2]; Francis, Samson ^[3]; Chirapu, Srinivas ^[4]; Finn, M. G. ^[4]; Zlotnick, Adam ^[1]

Indiana Univ., Bloomington, IN (United States)
Assembly Biosciences, Bloomington, IN (United States); Assembly Biosciences, San Francisco, CA (United States)
Indiana Univ., Bloomington, IN (United States); Assembly Biosciences, Bloomington, IN (United States); Assembly Biosciences, San Francisco, CA (United States)
The Scripps Research Inst., La Jolla, CA (United States); Georgia Inst. of Technology, Atlanta, GA (United States)

Though the hepatitis B virus (HBV) core protein is an important participant in many aspects of the viral life cycle, its best-characterized activity is self-assembly into 240-monomer capsids. Small molecules that target core protein (core protein allosteric modulators [CpAMs]) represent a promising antiviral strategy. To better understand the structural basis of the CpAM mechanism, we determined the crystal structure of the HBV capsid in complex with HAP18. HAP18 accelerates assembly, increases protein-protein association more than 100-fold, and induces assembly of nonicosahedral macrostructures. In a preformed capsid, HAP18 is found at quasiequivalent subunit-subunit interfaces. In a detailed comparison to the two other extant CpAM structures, we find that the HAP18-capsid structure presents a paradox. Whereas the two other structures expanded the capsid diameter by up to 10 Å, HAP18 caused only minor changes in quaternary structure and actually decreased the capsid diameter by ~3 Å. These results indicate that CpAMs do not have a single allosteric effect on capsid structure. We suggest that HBV capsids present an ensemble of states that can be trapped by CpAMs, indicating a more complex basis for antiviral drug design. Hepatitis B virus core protein has multiple roles in the viral life cycle—assembly, compartment for reverse transcription, intracellular trafficking, and nuclear functions—making it an attractive antiviral target. Core protein allosteric modulators (CpAMs) are an experimental class of antivirals that bind core protein. The most recognized CpAM activity is that they accelerate core protein assembly and strengthen interactions between subunits. In this study, we observe that the CpAM-binding pocket has multiple conformations. We compare structures of capsids cocrystallized with different CpAMs and find that they also affect quaternary structure in different ways. Furthermore, these results suggest that the capsid “breathes” and is trapped in different states by the drug and crystallization. Understanding that the capsid is a moving target will aid drug design and improve our understanding of HBV interaction with its environment.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); HHS; National Institutes of Health (NIH); National Inst. of Allergy and Infectious Diseases (NIAID)

Grant/Contract Number:: W31-109-Eng-38; R01 AI067417

OSTI ID:: 1247336

Journal Information:: Journal of Virology, Vol. 90, Issue 8; ISSN 0022-538X

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 51 works

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