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首页> 外文期刊>The FEBS journal >Direct detection of neuropeptide dynorphin A bindingto the second extracellular loop of the j opioid receptorusing a soluble protein scaffold
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Direct detection of neuropeptide dynorphin A bindingto the second extracellular loop of the j opioid receptorusing a soluble protein scaffold

机译：使用可溶性蛋白支架直接检测神经肽强啡肽A与j阿片受体第二个细胞外环的结合

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摘要

The molecular determinants for selectivity of ligand binding to membranereceptors are of key importance for the understanding of cellular signalling,as well as for rational therapeutic intervention. In the present study, wetarget the interaction between the j opioid receptor (KOR) and its nativepeptide ligand dynorphin A (DynA) using solution state NMR spectroscopy,which is generally made difficult by the sheer size of membranebound receptors. Our method is based on ‘transplantation’ of an extracellularloop of KOR into a ‘surrogate’ scaffold; in this case, a soluble b-barrel.Our results corroborate the general feasibility of the method, showingthat the inserted receptor segment has negligible effects on the propertiesof the scaffold protein, at the same time as maintaining an ability to bindits native DynA ligand. Upon DynA binding, only small induced chemicalshift changes of the KOR loop were observed, whereas chemical shiftchanges of DynA and NMR paramagnetic relaxation data show conclusivelythat the peptide interacts with the inserted loop. The binding interfaceis composed of a disordered part of the KOR loop and involves bothelectrostatic and hydrophobic interactions. Even so, simultaneous effectsalong the DynA sequence upon binding show that control of the recognitionis a concerted event.
机译：配体与膜受体结合的选择性的分子决定因素对于理解细胞信号以及合理的治疗干预至关重要。在本研究中，我们使用溶液状态NMR光谱法研究了阿片类药物受体（KOR）与它的天然肽配体强啡肽A（DynA）之间的相互作用，这通常由于膜结合受体的巨大尺寸而变得困难。我们的方法基于将KOR的细胞外环“移植”到“替代”支架中。我们的结果证实了该方法的一般可行性，表明插入的受体片段对支架蛋白特性的影响可忽略不计，同时保持了与天然DynA配体的结合能力。在DynA结合后，仅观察到了KOR环的微小化学位移变化，而DynA和NMR顺磁弛豫数据的化学位移变化最终表明该肽与插入的环发生相互作用。结合界面由KOR环的无序部分组成，并且涉及静电和疏水相互作用。即使如此，结合后沿DynA序列的同时作用表明识别的控制是一致的事件。

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