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G蛋白偶联受体的神经肽Y的结合模式的结构见解及药物发育后果

肽激素在体内歧管活动的调节中发挥着重要作用。其中许多通过G蛋白偶联受体(GPCR)将其活性传递,这是如今最有前景的药物靶标。因此,阐明配体的结合模式至关重要。然而,几种小分子系统的表征得很好,而大型和柔性肽的配体结合仍然更具挑战性。除了配体结合和受体活化之外,已经显示间接机制来发挥寻址GPCR的药物的作用。这包括脱敏,内化,因此它们作为药物穿梭的潜在用途,例如,它们。在肿瘤靶向。因此,除了配体结合之外,必须解决内化并进行研究,包括诱捕招募。因此,必须解决配体结合,结构动力学和内化,并进行研究以解决G蛋白偶联的药物发育的受体。神经肽Y /胰多肽家族含有36个氨基酸肽,其在人中结合四种不同的所谓的Y受体。 By a combination of X-ray analysis, NMR, molecular modeling and cross-linking combined with mass spectrometry, we could recently identify the distinct binding modes of NPY to the Y1- and the Y2 receptors. We could further demonstrate that chemical modification of the ligand, including fluorescence labeling, lipidization, and PEGylation significantly modifies the trafficking of the ligand. By labeling of the receptor with a novel template-assisted ligation strategy, we can follow ligand/receptor complexes in living cells. Furthermore, we identified a different mode of arrestin binding and recruitment. Neuropeptide Y1 and Y2 receptors have been shown to play a relevant role in different tumors. In breast cancer we demonstrated that human Y1 receptors are addressable by peptide conjugates using 99mTc or 18F PET-tracers. We now designed Y1 receptor selective peptides linked to different toxophors. Furthermore, we characterized the mechanism of direct and peptide-mediated uptake of tubulysin-related toxins. In the field of tumor therapy, peptide-drug conjugates are already well accepted. However, the concept of receptor-mediated internalization and subsequent tissue specific intracellular application is not limited to the selective addressing of tumors. This may open up a new field of targeted therapy by mid-sized drugs.


作者:

Annette G Beck-Sorninger



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