Agonists and partial agonists of rhodopsin: retinals with ring modifications.
Agonists and partial agonists of rhodopsin: retinals with ring modifications.
复制标题
视紫红质激动剂和部分激动剂：具有环修饰的视网膜。
作者：
R. Vogel;F. Siebert;S. Lüdeke;A. Hirshfeld;M. Sheves
视色素视紫红质的激活是通过其视网膜发色团异构化为全反式几何构型来启动的，这将蛋白质的构象驱动到活性状态。我们已经研究了FTIR光谱的影响，一系列的修改在环上的活化过程中，并结合口袋内的分子相互作用的视网膜。在C1和C5处的环甲基基团的缺失或在二乙基或乙基-甲基无环类似物中的环的替换导致部分激动剂，其中Meta I和Meta II光产物之间的构象平衡从活性Meta II侧移动到非活性Meta I侧。虽然这些人工色素的Meta II态具有与天然Meta II相似的构象，但Meta I态是不同的。对视黄醛环的修饰对Glu 122在环结合口袋内的相互作用具有特别的影响，并且显示出在Meta II形成期间干扰Glu 134介导的质子摄取。我们进一步发现，在部分删除的环成分，从Meta I到Meta II的过渡的熵变的减少高达50%，而随之而来的减少的焓项不太明显。这些发现强调了环和环甲基的特别重要性，并在受体活化模型中进行了讨论。
Activation of the visual pigment rhodopsin is initiated by isomerization of its retinal chromophore to the all-trans geometry, which drives the conformation of the protein to the active state. We have examined by FTIR spectroscopy the impact of a series of modifications at the ring of retinal on the activation process and on molecular interactions within the binding pocket. Deletion of ring methyl groups at C1 and C5 or replacement of the ring in diethyl or ethyl-methyl acyclic analogues resulted in partial agonists, for which the conformational equilibrium between the Meta I and Meta II photoproduct is shifted from the active Meta II side to the inactive Meta I side. While the Meta II states of these artificial pigments had a conformation similar to those of native Meta II, the Meta I states were different. Modifications on the ring of retinal had a particular impact on the interaction of Glu 122 within the ring-binding pocket and are shown to interfere with the Glu 134-mediated proton uptake during formation of Meta II. We further found, upon partial deletion of ring constituents, a decrease of the entropy change of the transition from Meta I to Meta II by up to 50%, while the concomitant reduction of the enthalpy term was less pronounced. These findings underline the particular importance of the ring and the ring methyl groups and are discussed in a model of receptor activation.