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Inhibitor design for ribonuclease A: the binding of two 5′‐phosphate uridine analogues

Inhibitor design for ribonuclease A: the binding of two 5′‐phosphate uridine analogues In the quest for the rational design of selective and potent inhibitors for members of the pancreatic ribonuclease A (RNase A) family of biomedical interest, the binding of uridine 5′‐phosphate (U5P) and uridine 5′‐diphosphate (UDP) to RNase A have been investigated using kinetic studies and X‐ray crystallography. Both nucleotides are competitive inhibitors of the enzyme, with Ki values of 4.0 and 0.65 mM, respectively. They bind to the active site of the enzyme by anchoring two molecules connected to each other by hydrogen bonds and van der Waals interactions. While the first of the inhibitor molecules binds with its nucleobase in the pyrimidinyl‐binding subsite, the second is bound at the purine‐preferring subsite. The unexpected binding of a pyrimidine at the purine‐binding subsite has added new important elements to the rational design approach for the discovery of new potent inhibitors of the RNase A superfamily. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Crystallographica Section F Wiley

Inhibitor design for ribonuclease A: the binding of two 5′‐phosphate uridine analogues

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References (26)

Publisher
Wiley
Copyright
International Union of Crystallography, 2009
ISSN
1744-3091
eISSN
1744-3091
DOI
10.1107/S1744309109021423
pmid
19574636
Publisher site
See Article on Publisher Site

Abstract

In the quest for the rational design of selective and potent inhibitors for members of the pancreatic ribonuclease A (RNase A) family of biomedical interest, the binding of uridine 5′‐phosphate (U5P) and uridine 5′‐diphosphate (UDP) to RNase A have been investigated using kinetic studies and X‐ray crystallography. Both nucleotides are competitive inhibitors of the enzyme, with Ki values of 4.0 and 0.65 mM, respectively. They bind to the active site of the enzyme by anchoring two molecules connected to each other by hydrogen bonds and van der Waals interactions. While the first of the inhibitor molecules binds with its nucleobase in the pyrimidinyl‐binding subsite, the second is bound at the purine‐preferring subsite. The unexpected binding of a pyrimidine at the purine‐binding subsite has added new important elements to the rational design approach for the discovery of new potent inhibitors of the RNase A superfamily.

Journal

Acta Crystallographica Section F – Wiley

Published: Jul 1, 2009

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