Comparison of crystal and solution hemoglobin binding of selected antigelling agents and allosteric modifiers.
Comparison of crystal and solution hemoglobin binding of selected antigelling agents and allosteric modifiers.
复制标题
所选抗胶凝剂和变构调节剂的晶体和溶液血红蛋白结合的比较。
DOI：
10.1021/bi00468a022
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发表时间：
1990
期刊：
影响因子：
2.9
通讯作者：
Abraham,DJ
中科院分区：
文献类型：
--
作者：
Mehanna,AS;Abraham,DJ
1989年12月20日收到的修订版摘要：本文详细介绍了人血红蛋白A与一组卤代羧酸的综合结合研究（溶液和X射线），这些卤代羧酸被研究为潜在的抗镰状剂。据我们所知，这是第一次研究比较溶液和晶体结合的一系列化合物在类似的高盐条件下用于共结晶。所述化合物包括[（3，4-二氯苄基）氧基]乙酸、[（对溴苄基）氧基]乙酸、氯贝酸和苯扎贝特。结合位点的位置和立体化学已通过X射线晶体学建立，而结合位点的数量和亲和常数通过使用平衡透析测量。采用脱氧血红蛋白和碳一氧血红蛋白进行了低盐（50 mM）和高盐（2 M）浓度的溶液结合研究。得出的结论是，所观察到的晶体结构与在溶液中观察到的结合是一致的，并且结合位点的数量与盐浓度无关，而结合常数随着盐浓度的增加而增加。研究还表明，药物分子化学结构的相对较小的变化可能导致蛋白质上完全不同的结合位点。此外，X-射线研究提供了一个可能的解释，这些化合物作为变构调节剂和/或抗枯萎剂所表现出的功能的多样性。最后，研究表明，这些化合物与血红蛋白的R和T状态的结合方式不同，这一观察结果对这些药物的原始设计具有特殊意义。
Revised Manuscript Received December 20, 1989 abstract: This paper details comprehensive binding studies (solution and X-ray) of human hemoglobin A with a group of halogenated carboxylic acids that were investigated as potential antisickling agents. It is, to our knowledge, the first study to compare solution and crystal binding for a series of compounds under similar high-salt conditions used for cocrystallization. The compounds include [(3, 4-dichlorobenzyl) oxy] acetic acid,[(p-bromobenzyl) oxy] acetic acid, clofibric acid, and bezafibrate. The location and stereochemistry of binding sites have been established by X-ray crystallography, while the number of binding sites and affinity constants were measured by using equilibrium dialysis. The solution binding studies were conducted with deoxygenated hemoglobin and carbonmonoxyhemoglobin with low (50 mM) and high (2 M) salt concen-trations. It was concluded that the observed crystal structures are consistent with the binding observed in solution and that the number of binding sites is independent of salt concentration, while the binding constant increases with increasing salt concentration. The studies also reveal that relatively small changes in the chemical structure of a drug molecule can result in entirely different binding sites on the protein. Moreover, the X-ray studies provide a possible explanation for the multiplicity in function exhibited by these compounds as allosteric modulators and/or antisickling agents. Finally, the studies indicate that these compoundsbind differently to the R and T states of hemoglobin, an observation of special significance to the original design of these agents.