Structures that delineate orphanin FQ and dynorphin A pharmacological selectivities
Structures that delineate orphanin FQ and dynorphin A pharmacological selectivities
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DOI：
10.1074/jbc.273.3.1490
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发表时间：
1998-01-16
影响因子：
4.8
通讯作者：
Civelli, O
中科院分区：
文献类型：
--
作者：
Reinscheid, RK;Higelin, J;Civelli, O
在结构相关的配体和受体的家庭严格的药理学选择性可能会导致在进化中的一个关键过程，旨在增加神经传递的多样性。当与阿片系统比较时，可以在新发现的孤啡肽（OFQ）系统中发现这种排他性特异性的有趣例子，OFQ及其受体分别与阿片肽及其相应受体具有高度的序列相似性，然而，OFQ不激活阿片受体，阿片肽也不引起OFQ受体的生物活性，因此，我们研究了OFQ和强啡肽A（其最接近的对应物）的一级结构的固有选择性的基础。一系列截短和/或嵌合肽导致以下结论：两种肽都含有建立其药理学选择性的结构域，在OFQ分子中，我们可以描绘出一个结构域，该结构域通过明显排斥其结合来阻止其激活卡帕阿片受体的能力。在这两种肽中，产生选择性的结构域由关键位置的单个残基以及不重叠的短段氨基酸组成。为了证明这一点，我们设计了一种通用激动剂，并发现它对OFQ受体和κ阿片受体都有活性。我们的观察表明，一种协调的进化机制将FQ系统与阿片系统分开。
Strict pharmacological selectivity in families of structurally related ligands and receptors may result from a key process in evolution aiming at increasing diversity in neurotransmission. An intriguing example of such exclusive specificity can be found in the newly discovered orphanin FQ (OFQ) system when it is compared with the opioid system, Both OFQ and its receptor share a high degree of sequence similarity to the opioid peptides and their corresponding receptors, respectively, However, OFQ does not activate opioid receptors, nor do the opioid peptides elicit biological activity at the OFQ receptor, We have therefore investigated the basis for the inherent selectivity of the primary structures of OFQ and dynorphin A, its closest counterpart, A series of truncated and/or chimeric peptides led to the conclusion that both peptides contain domains which establish their pharmacological selectivity, In the OFQ molecule we could delineate a domain that prevents its ability to activate the kappa-opioid receptor by apparently repelling its binding. In both peptides the selectivity-generating domains are composed of single residues in key positions together with short stretches of amino acids which do not overlap. To prove this concept, we designed a universal agonist and found it active at both the OFQ receptor and the kappa-opioid receptor, Our observations suggest that a coordinated mechanism of evolution has separated the orphanin FQ system from the opioid system.