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首页> 外文期刊>Biochemistry >Interactions outside the boundaries of the canonical binding groove of a pdz domain influence ligand binding
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Interactions outside the boundaries of the canonical binding groove of a pdz domain influence ligand binding

机译：pdz域的规范结合凹槽边界之外的相互作用影响配体结合

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摘要

The postsynaptic density protein-95/discs large/zonula occludens-1 (PDZ) domain is a protein-protein interaction module with a shallow binding groove where protein ligands bind. However, interactions that are not part of this canonical binding groove are likely to modulate peptide binding. We have investigated such interactions beyond the binding groove for PDZ3 from PSD-95 and a peptide derived from the C-terminus of the natural ligand CRIPT. We found via nuclear magnetic resonance experiments that up to eight residues of the peptide ligand interact with the PDZ domain, showing that the interaction surface extends far outside of the binding groove as defined by the crystal structure. PDZ3 contains an extra structural element, a C-terminal helix (α3), which is known to affect affinity. Deletion of this helix resulted in the loss of several intermolecular nuclear Overhauser enhancements from peptide residues outside of the binding pocket, suggesting that α3 forms part of the extra binding surface in wild-type PDZ3. Site-directed mutagenesis, isothermal titration calorimetry, and fluorescence intensity experiments confirmed the importance of both α3 and the N-terminal part of the peptide for the affinity. Our data suggest a general mechanism in which different binding surfaces outside of the PDZ binding groove could provide sites for specific interactions.
机译：突触后密度蛋白95 /盘大/小带闭塞1（PDZ）域是一种蛋白质-蛋白质相互作用模块，具有较浅的结合槽，蛋白质配体结合在该处。但是，不属于该常规结合槽的相互作用可能会调节肽结合。我们已经研究了来自PSD-95的PDZ3和天然配体CRIPT的C末端衍生的肽的结合槽之外的此类相互作用。我们通过核磁共振实验发现，肽配体的多达8个残基与PDZ域相互作用，表明相互作用表面延伸到结合槽外部，如晶体结构所定义。 PDZ3包含一个额外的结构元素，即C末端螺旋（α3），已知会影响亲和力。该螺旋的缺失导致结合口袋外部的肽残基丧失了分子间核Overhauser增强作用，这表明α3形成了野生型PDZ3中额外结合表面的一部分。定点诱变，等温滴定热法和荧光强度实验证实了α3和肽的N末端部分对于亲和力的重要性。我们的数据提出了一种通用机制，其中PDZ绑定凹槽之外的不同绑定表面可以提供特定相互作用的位点。

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