Morton A, Matthews B W
Institute of Molecular Biology, Howard Hughes Medical Institute, Eugene, Oregon, USA.
Biochemistry. 1995 Jul 11;34(27):8576-88. doi: 10.1021/bi00027a007.
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.
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，我们测定了一组结合在含腔的T4溶菌酶突变体中的配体的结构。可以看出内部腔由两部分组成，这两部分对配体结合的反应非常不同。首先，有一个相对刚性的区域，在结合任何配体时都不会显著松弛。其次，有一个更灵活的区域，它会根据结合不同配体而发生不同程度的移动。结合位点中保持刚性的部分具有低温因子和对氢交换的强保护作用。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）。更灵活的区域具有相对较高的温度因子和对氢交换的弱保护作用，通过以基本相同的能量成本进行不同程度的变形，允许在结合时有一定的混杂性。一方面，晶体学温度因子和氢交换行为所代表的动态信息与另一方面配体结合时的结构可塑性之间的这种联系，为提高我们对蛋白质核心和蛋白质-配体结合位点中空间相互作用的理解提供了一种方法。配体设计和堆积算法可能会利用这些信息，在蛋白质刚性的地方需要互补相互作用，而在蛋白质灵活的区域允许一些重叠。
