SmTAL1 is a calcium binding protein from the parasitic worm, Schistosoma mansoni. Structurally it is comprised of two domains - an N-terminal EF-hand domain and a C-terminal dynein light chain (DLC)-like domain. The protein has previously been shown to interact with the anti-schistosomal drug, praziquantel (PZQ). Here, we demonstrated that both EF-hands in the N-terminal domain are functional calcium ion binding sites. The second EF-hand appears to be more important in dictating affinity and mediating the conformational changes which occur on calcium ion binding. There is positive cooperativity between the four calcium ion binding sites in the dimeric form of SmTAL1. Both the EF-hand domain and the DLC-domain dimerise independently suggesting that both play a role in forming the SmTAL1 dimer. SmTAL1 binds non-cooperatively to PZQ and cooperatively to an IQ-motif from SmCav1B, a voltage-gated calcium channel. PZQ tends to strengthen this interaction, although the relationship is complex. These data suggest the hypothesis that SmTAL1 regulates at least one voltage-gated calcium channel and PZQ interferes with this process. This may be important in the molecular mechanism of this drug. It also suggests that compounds which bind SmTAL1, such as six from the Medicines for Malaria Box identified in this work, may represent possible leads for the discovery of novel antagonists.

中文翻译：

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曼氏血吸虫外皮过敏原蛋白SmTAL1：通过电压门控离子通道与吡喹酮的作用结合到IQ基序。

SmTAL1是来自寄生虫曼氏血吸虫的钙结合蛋白。在结构上，它由两个结构域组成-N端EF-手结构域和C端达因轻链（DLC）样结构域。该蛋白质先前已显示与抗血吸虫药物吡喹酮（PZQ）相互作用。在这里，我们证明了N末端域中的两个EF手都是功能性钙离子结合位点。第二支EF手似乎在指示亲和力和介导钙离子结合时发生的构象变化方面更为重要。SmTAL1的二聚体形式的四个钙离子结合位点之间具有正的协同作用。EF手域和DLC域二聚体均独立表明这两者均在形成SmTAL1二聚体中起作用。SmTAL1非合作地与PZQ绑定，并与SmCav1B（电压门控钙通道）的IQ-基序合作。尽管关系复杂，但PZQ倾向于加强这种交互。这些数据表明SmTAL1调节至少一个电压门控钙通道和PZQ干扰这一过程的假设。这在该药物的分子机制中可能很重要。这也表明与SmTAL1结合的化合物，例如在这项工作中鉴定出的六种来自疟疾药盒的药物，可能代表了发现新型拮抗剂的可能线索。这些数据表明SmTAL1调节至少一个电压门控钙通道和PZQ干扰这一过程的假设。这在该药物的分子机制中可能很重要。这也表明与SmTAL1结合的化合物，例如在这项工作中鉴定出的六种来自疟疾药盒的药物，可能代表了发现新型拮抗剂的可能线索。这些数据表明SmTAL1调节至少一个电压门控钙通道和PZQ干扰这一过程的假设。这在该药物的分子机制中可能很重要。这也表明与SmTAL1结合的化合物，例如在这项工作中鉴定出的六种来自疟疾药盒的药物，可能代表了发现新拮抗剂的可能线索。