Williamson R M
Department of Biotechnology, Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48106-1047, USA.
J Theor Biol. 1995 May 21;174(2):179-88. doi: 10.1006/jtbi.1995.0090.
Determining how specificity for a given ligand occurs among sequence and structurally related transporters is a fundamental problem in elucidating facilitated transport. It is likely that the specificity of a transporter for a ligand is defined by the primary amino acid sequence, and that different ligand specificities among highly related proteins are associated with variations in the amino acid sequence. To assist studies on the potential relationships between protein structure and ligand specificity, information theory was used to assign a measure that quantitates the importance of amino acid choice at individual sites in protein sequences based upon their variability. The approach allows for the transformation of a collection of multiply aligned sequences into a profile that provides a quantitative assessment of the relative frequencies of chemically similar residues at each site. Profiles generated from particular groups of proteins can be directly compared to profiles generated for other groups. These comparisons allow unique differences in the utilization of amino acids at individual sites to be identified as differences in information distribution. The approach was applied to the problem of identifying sites of the dopamine transporter which may play a role in distinguishing its ligand specificity and function from those of a related population of transporters for amino acid and amino-acid-like ligands. Several sites were identified that appear highly likely to distinguish the dopamine transporter from related proteins. Many of the sites identified were also found to be associated with predicted variations in local secondary and tertiary structure between the two classes of proteins.
确定在序列和结构相关的转运蛋白中，针对特定配体的特异性是如何产生的，这是阐明易化转运过程中的一个基本问题。转运蛋白对配体的特异性很可能是由一级氨基酸序列决定的，而且高度相关蛋白质之间不同的配体特异性与氨基酸序列的变化有关。为了辅助研究蛋白质结构与配体特异性之间的潜在关系，信息论被用于指定一种度量方法，该方法基于氨基酸序列中各个位点的变异性来量化氨基酸选择的重要性。这种方法可以将多个比对序列的集合转化为一个图谱，该图谱对每个位点化学性质相似的残基的相对频率进行定量评估。从特定蛋白质组生成的图谱可以直接与为其他蛋白质组生成的图谱进行比较。这些比较使得能够将各个位点氨基酸利用上的独特差异识别为信息分布上的差异。该方法被应用于识别多巴胺转运蛋白中可能在区分其配体特异性和功能与相关氨基酸及氨基酸类似物配体转运蛋白群体的配体特异性和功能方面发挥作用的位点。识别出了几个似乎极有可能将多巴胺转运蛋白与相关蛋白质区分开来的位点。还发现许多识别出的位点与两类蛋白质之间局部二级和三级结构的预测变化有关。
