Common and divergent structural features of a series of corticotropin releasing factor-related peptides
Common and divergent structural features of a series of corticotropin releasing factor-related peptides
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DOI：
10.1021/ja0760933
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发表时间：
2007-12-26
影响因子：
15
通讯作者：
Riek, Roland
中科院分区：
文献类型：
--
作者：
Grace, Christy Rani R.;Perrin, Marilyn H.;Riek, Roland
皮质释放素家族的成员包括促肾上腺皮质激素释放因子（CRF）、sauvagine、尿紧张素和尿皮质素1（Ucn 1），它们与CRF受体CRF-R1和CRF-R2结合，以及尿皮质素2（Ucn 2）和3（Ucn 3），它们是CRF-R2的选择性激动剂。构效关系的研究导致了几个有效的和长效的类似物与选择性结合的受体之一。在DMSO中测定了该家族六种配体（拮抗剂astressin B和astressin（2）-B、激动剂stressin（1）以及天然配体人Ucn 1、Ucn 2和Ucn 3）的NMR结构。这六种肽在结合亲和力、受体选择性和NMR结构方面显示出差异。总的来说，他们的骨干是一个。螺旋的，在残基25 - 27周围具有小的扭结或转弯，导致螺旋-环-螺旋基序。C-末端螺旋具有两亲性，而N-末端螺旋的两亲性不同。因此，C-末端螺旋的构象非常类似于我们小组最近报道的与CRF-R2的ECD 1结合的astressin的构象。(1)观察到的[Ala]-取代的类似物的3D结构和相对效力的分析的基础上，它建议，这两个螺旋可以发挥至关重要的作用，受体结合和选择性。总之，C-末端螺旋可能沿着它们的疏水表面与ECD 1相互作用，而整个N-末端螺旋表面可能参与受体活化。在这些配体的三维结构中观察到的共同和不同的功能的基础上，提出了多个结合模型，可以解释他们的多个行动。
Members of the corticoliberin family include the corticotropin releasing factors (CRFs), sauvagine, the urotensins, and urocortin 1 (Ucn1), which bind to both the CRF receptors CRF-R1 and CRF-R2, and the urocortins 2 (Ucn2) and 3 (Ucn3), which are selective agonists of CRF-R2. Structure activity relationship studies led to several potent and long-acting analogues with selective binding to either one of the receptors. NMR structures of six ligands of this family (the antagonists astressin B and astressin(2)-B, the agonists stressin(1), and the natural ligands human,Ucn1, Ucn2, and Ucn3) were determined in DMSO. These six peptides show differences in binding affinities, receptor-selectivity, and NMR structure. Overall, their backbones are a.-helical, with a small kink or a turn around residues 25 - 27, resulting in a helix - loop - helix motif. The C-terminal helices are of amphipathic nature, whereas the N-terminal helices vary in their amphipathicity. The C-terminal helices thereby assume a conformation very similar to that of astressin bound to the ECD1 of CRF-R2 recently reported by our group.(1) On the basis of an analysis of the observed 3D structures and relative potencies of [Ala]-substituted analogues, it is proposed that both helices could play a crucial role in receptor binding and selectivity. In conclusion, the C-terminal helices may interact along their hydrophobic faces with the ECD1, whereas the entire N-terminal helical surface may be involved in receptor activation. On the basis of the common and divergent features observed in the 3D structures of these ligands, multiple binding models are proposed that may explain their plurality of actions.