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Crystal structure of Hepatitis B virus T=4 capsid in complex with the allosteric modulator HAP18
Structural highlights
FunctionCAPSD_HBVD1 Self assembles to form an icosahedral capsid. Most capsid appear to be large particles with a icosahedral symmetry of T=4 and consist of 240 copies of capsid protein, though a fraction forms smaller T=3 particles consisting of 180 capsid proteins. Entering capsid are transported along microtubules to the nucleus. Phosphorylation of the capsid is thought to induce exposure of nuclear localization signal in the C-terminal portion of the capsid protein that allows binding to the nuclear pore complex via the importin (karyopherin-) alpha and beta. Capsids are imported in intact form through the nuclear pore into the nuclear basket, where it probably binds NUP153. Only capsids that contain the mature viral genome can release the viral DNA and capsid protein into the nucleoplasm. Immature capsids get stucked in the basket. Capsids encapsulate the pre-genomic RNA and the P protein. Pre-genomic RNA is reverse transcribed into DNA while the capsid is still in the cytoplasm. The capsid can then either be directed to the nucleus, providing more genome for transcription, or bud through the endoplasmic reticulum to provide new virions (By similarity).[1] Encapsidates hepatitis delta genome (By similarity).[2] Publication Abstract from PubMedThough 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. References
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