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Publication Abstract from PubMed

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 CpAM mechanism, we determined the crystal structure of the HBV capsid in complex with HAP18. HAP18 accelerates assembly, increases protein-protein association by more than 100-fold, and induces assembly of non-icosahedral macro-structures. In a preformed capsid, HAP18 is found at quasi-equivalent subunit-subunit interfaces. In detailed comparison to the two other extant CpAM structures, we find that the HAP18-capsid structure presents a paradox. Where the two other structures expanded the capsid diameter by up to 10A, HAP18 caused only minor changes in quaternary structure and actually decreased capsid diameter by approximately 3A. 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. IMPORTANCE: Hepatitis B Virus core protein has multiple roles in the viral lifecycle - assembly, compartment for reverse transcription, intracellular trafficking, nuclear functions - making it an attractive antiviral target. Core protein allosteric modulators (CpAMs), are an experimental class of antiviral that bind core protein. The most accessible 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 co45 crystallized with different CpAMs and find that they also affect quaternary structure in different ways. 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.

Hepatitis B virus capsids have diverse structural responses to small molecule ligands bound to the HAP pocket.,Venkatakrishnan B, Katen SP, Francis S, Chirapu S, Finn MG, Zlotnick A J Virol. 2016 Feb 3. pii: JVI.03058-15. PMID:26842475^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.