Structural insights into the HBV receptor and bile acid transporter NTCP

B型肝炎ウイルスの受容体“胆汁酸輸送体”の立体構造を解明. 京都大学プレスリリース. 2022-05-18.Roughly 250 million people are infected with hepatitis B virus (HBV) worldwide, and perhaps 15 million also carry the satellite virus HDV, which confers even greater risk of severe liver disease. Almost ten years ago the HBV receptor was identified as NTCP (sodium taurocholate co-transporting polypeptide), which interacts directly with the first 48 amino acid residues of the N-myristoylated N-terminal preS1 domain of the viral large (L) protein. Despite the pressing need for therapeutic agents to counter HBV, the structure of NTCP remains unsolved. This 349-residue protein is closely related to human apical sodium-dependent bile acid transporter (ASBT), another member of the solute carrier family SLC10. Crystal structures have been reported of similar bile acid transporters from bacteria, and these models with ten transmembrane helices are believed to resemble strongly both NTCP and ASBT. Using cryo-electron microscopy we have solved the structure of NTCP bound to an antibody, clearly showing the transporter has no equivalent to the first transmembrane helix of other SLC10 models, leaving the N-terminus exposed on the extracellular face. Comparison of the different structures indicates a common mechanism of bile acid transport, but the NTCP structure also displays a pocket formed by residues known to interact with preS1, presenting new and enticing opportunities for structure-based drug design

Troglitazone Impedes the Oligomerization of Sodium Taurocholate Cotransporting Polypeptide and Entry of Hepatitis B Virus Into Hepatocytes

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A new strategy to identify hepatitis B virus entry inhibitors by AlphaScreen technology targeting the envelope-receptor interaction

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Cytotoxic effects of K-7174 on bortezomib-resistant MM cells.

<p>We established wild-type (WT) and mutant (mutant) sublines from RPMI8226 by transducing with wild-type and mutated <i>PSMB5</i> cDNA, respectively, and analyzed the expression of VENUS by flow cytometry (A) and proteasome ß5 subunit by immunoblotting (B). The signal intensities of ß5 subunit (PSMB5) were quantified, normalized to those of the corresponding GAPDH, and shown as relative values in the panel B. C. Cell proliferation was measured by MTT assays after culturing each subline with either K-7174 or bortezomib at the indicated doses for 72 hours. Results are represented as relative absorbance with untreated control set at 100%. The means ± S.D. (bars) of three independent experiments are shown. <i>P</i>-values were calculated by one-way ANOVA with the Student-Newman-Keuls multiple comparisons test. Asterisks indicate p<0.01 against the WT subline. D. Each subline was cultured with either K-7174 or bortezomib (Bort) at the indicated doses for 48 hours. Whole cell lysates were subjected to immunoblotting for cellular protein ubiquitination, proteasome ß5 subunit (PSMB5) and GAPDH (internal control).</p