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首页> 外文期刊>Acta crystallographica.Section D. Biological crystallography >Binding of flexible and constrained ligands to the Grb2 SH2 domain: structural effects of ligand preorganization.
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Binding of flexible and constrained ligands to the Grb2 SH2 domain: structural effects of ligand preorganization.

机译：绑定的灵活和受限的配体域:Grb2 SH2结构配位体的影响preorganization。

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Structures of the Grb2 SH2 domain complexed with a series of pseudopeptides containing flexible (benzyl succinate) and constrained (aryl cyclopropanedicarboxylate) replacements of the phosphotyrosine (pY) residue in tripeptides derived from Ac-pYXN-NH(2) (where X = V, I, E and Q) were elucidated by X-ray crystallography. Complexes of flexible/constrained pairs having the same pY + 1 amino acid were analyzed in order to ascertain what structural differences might be attributed to constraining the phosphotyrosine replacement. In this context, a given structural dissimilarity between complexes was considered to be significant if it was greater than the corresponding difference in complexes coexisting within the same asymmetric unit. The backbone atoms of the domain generally adopt a similar conformation and orientation relative to the ligands in the complexes of each flexible/constrained pair, although there are some significant differences in the relative orientations of several loop regions, most notably in the BC loop that forms part of the binding pocket for the phosphate group in the tyrosine replacements. These variations are greater in the set of complexes of constrained ligands than in the set of complexes of flexible ligands. The constrained ligands make more direct polar contacts to the domain than their flexible counterparts, whereas the more flexible ligand of each pair makes more single-water-mediated contacts to the domain; there was no correlation between the total number of protein-ligand contacts and whether the phosphotyrosine replacement of the ligand was preorganized. The observed differences in hydrophobic interactions between the complexes of each flexible/constrained ligand pair were generally similar to those observed upon comparing such contacts in coexisting complexes. The average adjusted B factors of the backbone atoms of the domain and loop regions are significantly greater in the complexes of constrained ligands than in the complexes of the corresponding flexible ligands, suggesting greater thermal motion in the crystalline state in the former complexes. There was no apparent correlation between variations in crystal packing and observed structural differences or similarities in the complexes of flexible and constrained ligands, but the possibility that crystal packing might result in structural variations cannot be rigorously excluded. Overall, it appears that there are more variations in the three-dimensional structure of the protein and the ligand in complexes of the constrained ligands than in those of their more flexible counterparts.
机译：的Grb2 SH2结构域包裹着一系列pseudopeptides包含灵活(琥珀酸苄酯)和约束(芳基cyclopropanedicarboxylate)的替代品phosphotyrosine (pY)残留在三肽来自Ac-pYXN-NH (2) (X = V, I, E和问)被x射线晶体学阐明。复合物的灵活/约束对拥有相同的pY + 1氨基酸进行了分析确定结构上的差异可能是什么归因于phosphotyrosine约束更换。复合物被认为之间的不同如果是大于水平具有重要意义对应不同的复合物共存在相同的不对称单元。原子域通常采用类似构象和方向相对配合物的配体灵活的/约束对,虽然有一些重要差异相对的方向的几个循环区域,最多尤其是在BC循环的一部分口袋里的磷酸基有约束力酪氨酸替代品。更大的复合体的限制配体复合物的设置灵活配体。极地接触域比他们的灵活同行,而更多的灵活的配体每一对更single-water-mediated接触域;protein-ligand总数之间的关系接触和phosphotyrosine更换preorganized配体。观察不同的疏水相互作用之间的配合物灵活的/限制配体对一般所观察到的类似这样的比较联系人在共存复合物。调整因素的骨干原子域和循环区域明显更大在配合物的配体比的限制相应的灵活的复合物配体,表明更大的热运动在前复合物结晶状态。没有明显相关性的变化水晶包装和观察到的结构配合物的差异和相似之处灵活和受限的配体,但是水晶包装可能导致的可能性不能严格的结构变化排除在外。三维结构的变化蛋白质和配体的配合物限制配体比的更多灵活的同行。

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