小柯机器人

日本横滨市大学Sam-Yong Park和韩国延世大学Weontae Lee研究团队共同合作近期取得重要工作进展。他们对HBV受体和胆汁酸转运体NTCP的结构进行了深入的研究。该项成果2022年5月17日在线发表于《自然》杂志上。

研究人员通过使用冷冻电子显微镜，已经解析了与抗体结合的NTCP的结构，清楚地表明转运蛋白没有相当于其他SLC10模型的第一个跨膜螺旋，使N端暴露在细胞外。不同结构的比较表明胆汁酸转运的共同机制，但NTCP结构也显示出了已知与preS1相互作用的残基形成的口袋，为基于结构的药物设计提供了新的诱人机会。

据介绍，全世界大约有2.5亿人感染了乙型肝炎病毒（HBV），可能还有1500万人还携带卫星病毒HDV，这会增加患严重肝病的风险。大约十年前，HBV受体被鉴定为NTCP（牛磺胆酸钠协同转运多肽），它直接与病毒大（L）蛋白的N-肉豆蔻酰化N-末端preS1结构域的前 48个氨基酸残基相互作用。尽管迫切需要治疗药物来对抗HBV，但NTCP的结构仍未得到解决。这种含有349个残基的蛋白质与人顶端钠依赖性胆汁酸转运蛋白（ASBT）密切相关，ASBT是溶质载体家族SLC10的另一个成员。已经报道了来自细菌的类似胆汁酸转运蛋白的晶体结构，并且这些具有十个跨膜螺旋的模型被认为与NTCP和ASBT非常相似。

附：英文原文

Title: Structural insights into the HBV receptor and bile acid transporter NTCP

Author: Park, Jae-Hyun, Iwamoto, Masashi, Yun, Ji-Hye, Uchikubo-Kamo, Tomomi, Son, Donghwan, Jin, Zeyu, Yoshida, Hisashi, Ohki, Mio, Ishimoto, Naito, Mizutani, Kenji, Oshima, Mizuki, Muramatsu, Masamichi, Wakita, Takaji, Shirouzu, Mikako, Liu, Kehong, Uemura, Tomoko, Nomura, Norimichi, Iwata, So, Watashi, Koichi, Tame, Jeremy R. H., Nishizawa, Tomohiro, Lee, Weontae, Park, Sam-Yong

Issue&Volume: 2022-05-17

Abstract: Roughly 250 million people are infected with hepatitis B virus (HBV) worldwide1, and perhaps 15 million also carry the satellite virus HDV, which confers even greater risk of severe liver disease2. 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) protein3. 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 bacteria4, 5, 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.

DOI: 10.1038/s41586-022-04857-0

Source: https://www.nature.com/articles/s41586-022-04857-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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