Matthews D A, Alden R A, Freer S T, Xuong N, Kraut J
J Biol Chem. 1979 May 25;254(10):4144-51.
The NADPH molecule binds to dihydrofolate reductase in an extended conformation. Several of the individual dihedral angles, especially in the adenine mononucleotide portion of the coenzyme, differ from their minimum energy conformations. The ribose phosphate portions of the coenzyme are involved in numerous specific hydrogen-bonded and charge-charge interactions. The adenine ring resides in an apparently nonspecific hydrophobic cleft and the nicotinamide ring is bound within an intricately constructed cavity, one wall of which includes the pyrazine ring of bound methotrexate. Two rather extended loops (residues 10 to 24 and 117 to 135) connecting beta A to alpha B and beta F to beta G, respectively, move 2 to 3 A when NADPH binds to dihydrofolate reductase. No overall structural homology is evident between the dinucleotide binding domains of dihydrofolate reductase on the one hand and the four NAD+-dependent dehydrogenases of known structure on the other. However, binding does occur in both cases at the carboxyl edge of a region of parallel beta sheet flanked by a pair of alpha helices.
NADPH分子以伸展构象与二氢叶酸还原酶结合。几个二面角，特别是辅酶中腺嘌呤单核苷酸部分的二面角，与其最低能量构象不同。辅酶的核糖磷酸部分参与了众多特定的氢键和电荷-电荷相互作用。腺嘌呤环位于一个明显非特异性的疏水裂隙中，烟酰胺环则结合在一个结构复杂的腔内，该腔的一侧壁包含结合的甲氨蝶呤的吡嗪环。分别连接βA与αB以及βF与βG的两个相当伸展的环（残基10至24和117至135）在NADPH与二氢叶酸还原酶结合时移动2至3埃。一方面，二氢叶酸还原酶的二核苷酸结合结构域与另一方面已知结构的四种NAD⁺依赖性脱氢酶之间没有明显的整体结构同源性。然而，在这两种情况下，结合都发生在由一对α螺旋侧翼的平行β折叠区域的羧基边缘。
