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TitleStructural basis for hepatitis B virus restriction by a viral receptor homologue.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 9241, Year 2024
Publish dateOct 25, 2024
AuthorsKaho Shionoya / Jae-Hyun Park / Toru Ekimoto / Junko S Takeuchi / Junki Mifune / Takeshi Morita / Naito Ishimoto / Haruka Umezawa / Kenichiro Yamamoto / Chisa Kobayashi / Atsuto Kusunoki / Norimichi Nomura / So Iwata / Masamichi Muramatsu / Jeremy R H Tame / Mitsunori Ikeguchi / Sam-Yong Park / Koichi Watashi /
PubMed AbstractMacaque restricts hepatitis B virus (HBV) infection because its receptor homologue, NTCP (mNTCP), cannot bind preS1 on viral surface. To reveal how mNTCP loses the viral receptor function, we here ...Macaque restricts hepatitis B virus (HBV) infection because its receptor homologue, NTCP (mNTCP), cannot bind preS1 on viral surface. To reveal how mNTCP loses the viral receptor function, we here solve the cryo-electron microscopy structure of mNTCP. Superposing on the human NTCP (hNTCP)-preS1 complex structure shows that Arg158 of mNTCP causes steric clash to prevent preS1 from embedding onto the bile acid tunnel of NTCP. Cell-based mutation analysis confirms that only Gly158 permitted preS1 binding, in contrast to robust bile acid transport among mutations. As the second determinant, Asn86 on the extracellular surface of mNTCP shows less capacity to restrain preS1 from dynamic fluctuation than Lys86 of hNTCP, resulting in unstable preS1 binding. Additionally, presence of long-chain conjugated-bile acids in the tunnel induces steric hindrance with preS1 through their tailed-chain. This study presents structural basis in which multiple sites in mNTCP constitute a molecular barrier to strictly restrict HBV.
External linksNat Commun / PubMed:39455604 / PubMed Central
MethodsEM (single particle)
Resolution3.49 Å
Structure data

38240

8xcd

EMDB-38240, PDB-8xcd:
Macaca fascicularis NTCP in complex with YN69083 Fab
Method: EM (single particle) / Resolution: 3.49 Å

Chemicals

ChemComp-TCH:
TAUROCHOLIC ACID

Source
  • macaca fascicularis (crab-eating macaque)
  • mus musculus (house mouse)
KeywordsTRANSPORT PROTEIN/IMMUNE SYSTEM / transporter / transport protein-immune system complex

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