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<p>The preS1 domain present on hepatitis B and D virus particles is an intrinsically disordered peptide (IDP) essential for recognizing the host receptor, sodium taurocholate co-transporting polypeptide (NTCP). However, it remains poorly understood how the disordered preS1 peptide achieves high-affinity binding through its conformational change. Here, we reveal a stepwise binding process through which multiple regions within preS1 cooperate to establish the stable binding to NTCP. By combining structure-based molecular simulations with virological assays, we show that Asn9<sup>preS1</sup>, Gly12<sup>preS1</sup>, and His17<sup>preS1</sup> primarily mediate the NTCP binding by forming a tandem loop core structure that docks into the bile acid tunnel of NTCP, creating an extensive binding interface. Another interaction via Trp41<sup>preS1</sup> stabilizes the flexible preS1 33–48 aa stretch embedded onto the NTCP outerface, particularly involving Asn87<sup>NTCP</sup> and Tyr146<sup>NTCP</sup>. Mutation in these key residues abolishes virion infectivity in cell culture and mouse models, demonstrating the biological significance of this binding maturation. These findings propose a multistep mechanism for viral IDP-mediated receptor recognition that ensures high virion infectivity and strict host specificity.</p>

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Multistep receptor binding of the hepatitis B virus preS1 domain

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月30日

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  • Chisa Kobayashi,
  • Toru Ekimoto,
  • Koji Ooka,
  • Junki Mifune,
  • Kayo Matsuzawa,
  • Lusheng Que,
  • Yingfang Li,
  • Atsuto Kusunoki,
  • Takeshi Morita,
  • Kaho Shionoya,
  • Makoto Nagano,
  • Kousho Wakae,
  • Masanori Isogawa,
  • Masamichi Muramatsu,
  • Umeharu Ohto,
  • Norimichi Nomura,
  • Sam-Yong Park,
  • Camille Sureau,
  • Munehito Arai,
  • Mitsunori Ikeguchi,
  • Koichi Watashi

摘要

The preS1 domain present on hepatitis B and D virus particles is an intrinsically disordered peptide (IDP) essential for recognizing the host receptor, sodium taurocholate co-transporting polypeptide (NTCP). However, it remains poorly understood how the disordered preS1 peptide achieves high-affinity binding through its conformational change. Here, we reveal a stepwise binding process through which multiple regions within preS1 cooperate to establish the stable binding to NTCP. By combining structure-based molecular simulations with virological assays, we show that Asn9preS1, Gly12preS1, and His17preS1 primarily mediate the NTCP binding by forming a tandem loop core structure that docks into the bile acid tunnel of NTCP, creating an extensive binding interface. Another interaction via Trp41preS1 stabilizes the flexible preS1 33–48 aa stretch embedded onto the NTCP outerface, particularly involving Asn87NTCP and Tyr146NTCP. Mutation in these key residues abolishes virion infectivity in cell culture and mouse models, demonstrating the biological significance of this binding maturation. These findings propose a multistep mechanism for viral IDP-mediated receptor recognition that ensures high virion infectivity and strict host specificity.