| Autor: |
Jenkins, Cara L., Thiyagarajan, Nethaji, Sweeney, Rozamond Y., Guy, Michael P., Kelemen, Bradley R., Acharya, K. Ravi, Raines, Ronald T. |
| Předmět: |
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| Zdroj: |
FEBS Journal; Feb2005, Vol. 272 Issue 3, p744-755, 12p |
| Abstrakt: |
2′-Fluoro-2′-deoxyuridine 3′-phosphate (dUFMP) and arabinouridine 3′-phosphate (araUMP) have non-natural furanose rings. dUFMP and araUMP were prepared by chemical synthesis and found to have three- to sevenfold higher affinity than uridine 3′-phosphate (3′-UMP) or 2′-deoxyuridine 3′-phosphate (dUMP) for ribonuclease A (RNase A). These differences probably arise (in part) from the phosphoryl groups of 3′-UMP, dUFMP, and araUMP (pKa = 5.9) being more anionic than that of dUMP (pKa = 6.3). The three-dimensional structures of the crystalline complexes of RNase A with dUMP, dUFMP and araUMP were determined at< 1.7 Å resolution by X-ray diffraction analysis. In these three structures, the uracil nucleobases and phosphoryl groups bind to the enzyme in a nearly identical position. Unlike 3′-UMP and dUFMP, dUMP and araUMP bind with their furanose rings in the preferred pucker. In the RNase A·araUMP complex, the 2′-hydroxyl group is exposed to the solvent. All four 3′-nucleotides bind more tightly to wild-type RNase A than to its T45G variant, which lacks the residue that interacts most closely with the uracil nucleobase. These findings illuminate in atomic detail the interaction of RNase A and 3′-nucleotides, and indicate that non-natural furanose rings can serve as the basis for more potent inhibitors of catalysis by RNase A. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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