Division of Chemistry and Structural Biology, The University of Queensland, Institute for Molecular Bioscience, St Lucia, Brisbane, QLD 4072, Australia.
Division of Chemistry and Structural Biology, The University of Queensland, Institute for Molecular Bioscience, St Lucia, Brisbane, QLD 4072, Australia.
Trends Pharmacol Sci. 2014 May;35(5):219-26. doi: 10.1016/j.tips.2014.03.004. Epub 2014 Apr 16.
G-protein-coupled receptors (GPCRs) that recognize the lysophospholipids (LPLs) are grouped into two phylogenetically distinct families: the endothelial differentiation gene (Edg) and non-Edg GPCRs. Owing to their more recent identification, and hindered by a lack of selective pharmacological tools, our understanding of the functions and signaling pathways of the non-Edg GPCRs is still in its infancy. Targeting the non-conserved allosteric binding sites of the LPL GPCRs shows particular promise for the development of selective modulators by structure-based drug design. However, only one Edg GPCR (S1PR1) structure has been determined to date, and it has low sequence identity with the non-Edg GPCRs (<20%). Thus, a representative structure of a non-Edg GPCR remains a pressing objective for selective structure-based drug design. Obtaining selective modulators targeting the non-Edg receptors would help to unravel the biology behind these novel GPCRs and potentially will support therapeutic treatment of diseases such as cancer, inflammation, and neuropsychiatric disorders.
G 蛋白偶联受体 (GPCRs) 能够识别溶血磷脂 (LPLs)，它们被分为两个在进化上截然不同的家族：内皮分化基因 (Edg) 和非 Edg GPCRs。由于它们是最近才被发现的，并且缺乏选择性的药理学工具，因此我们对非 Edg GPCRs 的功能和信号通路的理解还处于起步阶段。通过基于结构的药物设计，针对 LPL GPCR 的非保守变构结合位点进行靶向，显示出开发选择性调节剂的特殊前景。然而，迄今为止只确定了一个 Edg GPCR（S1PR1）的结构，它与非 Edg GPCRs 的序列同一性较低（<20%）。因此，获得非 Edg GPCR 的代表性结构仍然是选择性基于结构的药物设计的紧迫目标。获得针对非 Edg 受体的选择性调节剂将有助于揭示这些新型 GPCR 的生物学基础，并可能支持癌症、炎症和神经精神疾病等疾病的治疗。
