Changes in the electron density of the cofactor NADPH on binding to E. coli dihydrofolate reductase.
Changes in the electron density of the cofactor NADPH on binding to E. coli dihydrofolate reductase.
复制标题
辅因子 NADPH 与大肠杆菌二氢叶酸还原酶结合时电子密度的变化。
DOI：
10.1002/prot.340110405
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发表时间：
1991
期刊：
影响因子：
2.9
通讯作者：
Hagler,AT
中科院分区：
文献类型：
--
作者：
Bajorath,J;Li,ZQ;Fitzgerald,G;Kitson,DH;Farnum,M;Fine,RM;Kraut,J;Hagler,AT
量子力学电子密度计算表明，辅因子 NADPH（还原烟酰胺腺嘌呤二核苷酸磷酸）与二氢叶酸还原酶结合时会产生显着的极化。计算表明，对应于 ∼0.7 个电子电荷的电子密度在分子内移动，延伸超过 20Å。对所提出的酶突变体的进一步计算表明，NADPH 与 DHFR 结合时的极化在很大程度上是由三个带正电残基的基序诱导的。该基序也被确定为直接导致酶中辅因子结合位点周围的正静电势的原因。 NADPH 这种长程极化的可能性最初是基于之前对配体与 DHFR 结合的研究提出的，其中发现三个带正电残基的保守结构基序在底物叶酸整个 18 Å 长度的极化中发挥着主要作用。
Quantum‐mechanical electron density calculations reveal that a significant polarization is induced in the cofactor NADPH (reduced nicotinamide adenine dinucleotide phosphate) on binding to the enzyme dihydrofolate reductase. The calculations indicate that electron density corresponding to ∼0.7 electron charges is shifted within the molecule, extending over more than 20Å. Further calculations on proposed enzyme mutants show that the polarization of NADPH on binding to DHFR is, in large part, induced by a motif of three positively charged residues. This motif was also identified to be directly responsible for the positive electrostatic potential surrounding the cofactor binding site in the enzyme. The possibility of this long‐range polarization of NADPH was originally proposed based on a previous study of ligand binding to DHFR where a conserved structural motif of three positively charged residues was found to play a major role in polarizing the substrate folate over its entire length of 18 Å.