{ "abstract": "In an infection, Hepatitis B Virus (HBV) core protein (HBc) normally assembles into icosahedral capsids. Capsid Assembly Modulators (CAMs) are direct acting antivirals that induce HBc mis-assembly and are the subject of active research and development. Two versions of HBc are used in structural studies of CAM-HBc complexes: Cp150 and Cp149-Y132A. Cp150 forms empty icosahedral capsids that are structurally indistinguishable from those found in virions. The Y132A mutation of Cp149 leads to an assembly defective soluble protein that crystalizes as flat hexagonal sheets, where the hexagons resemble icosahedral quasi-sixfold vertices. In this study, we compare structures of CAM-bound Cp150 to CAM-bound Cp149-Y132A. In capsids, the residues forming the CAM site shift to match the structure of bound CAMs, an induced fit. In Cp149-Y132A crystals, CAM sites show little structural adjustment in response to different CAMs binding. In turn, the array of residues that interact with CAMs varies from CAM to CAM in capsid structures but remains nearly constant in Cp149-Y132A crystals. These results illustrate important differences between CAM binding in Cp149-Y132A and Cp150 structures that will contribute to future CAM design. Author summary: Chronic Hepatitis B Virus (HBV) infection can lead to cirrhosis, liver failure, cancer, and death. There is a vaccine to prevent HBV infection, but there is no cure. One group of experimental agents that are attracting substantial effort are Capsid Assembly Modulators (CAMs). The HBV capsid is composed of 120 dimers of the HBV capsid protein (HBc). CAMs are small molecule assembly agonists that bind at dimer-dimer interfaces. CAM treatment leads to empty or aberrant capsids and suppresses formation of new virions. There are two systems used for CAM-HBc structural studies: assembly-active Cp150, which forms icosahedral particles, and assembly-inactive Cp149-Y132A, which is dimeric in solution but crystallizes to form sheets. In this study, we find systematic differences between CAM binding in Cp150 and Cp149-Y132A structures. In Cp150 structures, the CAM site adjusts to the shape of the CAM, an induced fit. In Cp149-Y132A the CAM sites change little in response to bound CAM. These findings will guide further development of CAMs towards a functional cure for chronic HBV.", "abstract_shown": true, "affiliations": [ "Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, Indiana, United States of America.", "Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware, United States of America." ], "article_type": "Research Article", "arxiv": null, "author_total": 4, "authors": [ { "affs": [ 0 ], "name": "Liam W Scott" }, { "affs": [ 1 ], "name": "Carolina Pérez-Segura" }, { "affs": [ 1 ], "name": "Jodi A Hadden-Perilla" }, { "affs": [ 0 ], "name": "Adam Zlotnick", "orcid": "0000-0001-9945-6267" } ], "bibtex": "https://research.draconitic.com/paper/f4yv43st5z87k.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014700", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014700", "id": "f4yv43st5z87k", "issns": [ "1553-7374", "1553-7366" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014700", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2713|Hepatitis B Virus Studies" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleic acids/RNA/RNA structure" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Hepatitis viruses/Hepatitis B virus" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral replication/Viral packaging" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral structure" ], [ "plos", "/Biology and life sciences/Molecular biology/Macromolecular structure analysis/RNA structure" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Hepatitis viruses/Hepatitis B virus" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Hepatitis viruses/Hepatitis B virus" ], [ "plos", "/Physical sciences/Chemistry/Physical chemistry/Chemical bonding/Hydrogen bonding" ], [ "plos", "/Physical sciences/Chemistry/Polymer chemistry/Dimers" ], [ "plos", "/Physical sciences/Materials science/Materials/Crystals" ], [ "plos", "/Physical sciences/Materials science/Materials/Oligomers/Dimers" ], [ "plos", "/Physical sciences/Physics/Condensed matter physics/Solid state physics/Crystallography/Crystal structure" ] ], "openalex": "W7221101990", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014700&type=printable", "pmcid": "PMC13705612", "pmid": "42853863", "published": "2026-10-09", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/f4yv43st5z87k.ris", "sources": [ { "first_seen": "2026-10-30T12:17:30Z", "native_id": "10.1371/journal.ppat.1014700", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014700" }, { "first_seen": "2026-10-30T12:18:12Z", "native_id": "MED:42853863", "source": "europepmc", "url": "https://europepmc.org/article/MED/42853863" } ], "subjects": [ { "field": "biology", "origin": "plos:microbiology", "subfield": "microbiology" }, { "field": "chemistry", "origin": "plos:polymer chemistry", "subfield": "materials-polymers" } ], "title": "Assembly-active and -inactive forms of HBV capsid protein provide distinctly different binding sites for capsid assembly modulators", "title_text": "Assembly-active and -inactive forms of HBV capsid protein provide distinctly different binding sites for capsid assembly modulators", "type": "peer-reviewed", "updated_at": "2026-10-30T12:18:12Z", "url": "https://research.draconitic.com/paper/f4yv43st5z87k", "venue": "PLOS Pathogens", "versions": [] }