SPECIFICITY OF LIGAND-BINDING IN A BURIED NONPOLAR CAVITY OF T4 LYSOZYME - LINKAGE OF DYNAMICS AND STRUCTURAL PLASTICITY
SPECIFICITY OF LIGAND-BINDING IN A BURIED NONPOLAR CAVITY OF T4 LYSOZYME - LINKAGE OF DYNAMICS AND STRUCTURAL PLASTICITY
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DOI：
10.1021/bi00027a007
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发表时间：
1995-07-11
期刊：
影响因子：
2.9
通讯作者：
MATTHEWS, BW
中科院分区：
文献类型：
--
作者：
MORTON, A;MATTHEWS, BW
为了更好地理解形状互补性在配体结合和蛋白质核心相互作用中的作用，已经确定了在 T4 溶菌酶的含空腔突变体中结合的一组配体的结构。内部空腔被认为由对配体结合做出非常不同反应的两部分组成。首先，有一个相对刚性的区域，在结合任何配体时不会显着松弛；其次，有一个更灵活的区域，可以响应不同配体的结合而进行不同程度的移动。保持刚性的结合位点部分的特点是低温因素和对氢交换的强大保护。该位点的这一部分似乎主要负责区分不同形状的配体（即，确定特异性）。更灵活的区域，其特征是相对较高的温度因素和较弱的氢交换保护，通过在基本相同的能量成本下经历不同量的变形，允许一些混杂的结合。一方面，由晶体温度因素表示的动态信息和氢交换行为之间的这种联系。另一方面，响应配体结合的结构可塑性，提出了一种提高我们对蛋白质核心和蛋白质-配体结合位点空间相互作用的理解的方法，配体设计和包装算法可能会利用这些信息，在蛋白质刚性的地方需要互补的相互作用，并在蛋白质柔性的区域允许一些重叠。
TO better understand the role of shape complementarity in ligand binding and protein core interactions, the structures have been determined of a set of ligands bound within a cavity-containing mutant of T4 lysozyme, The interior cavity is seen to consist of two parts that respond very differently to the binding of ligands, First, there is a relatively rigid region that does not relax significantly upon binding any ligand, Second, there is a more flexible region that moves to various extents in response to binding the different ligands. The part of the binding site that remains rigid is characterized by low temperature factors and strong protection from hydrogen exchange. This part of the site appears to be primarily responsible for discriminating between ligands of different shape (i.e., for determining specificity). The more flexible region, characterized by relatively high temperature factors and weak protection from hydrogen exchange, allows some promiscuity in binding by undergoing variable amounts of deformation at essentially the same energetic cost, This linkage between the dynamic information represented by crystallographic temperature factors and hydrogen-exchange behavior on the one hand. and structural plasticity in response to ligand binding on the other hand, suggests a way to improve our understanding of steric interactions in protein cores and protein-ligand binding sites, Ligand design and packing algorithms might take advantage of this information, requiring complementary interactions where the protein is rigid and allowing some overlap in regions where the protein is flexible.