1qhc Citations

Toward rational design of ribonuclease inhibitors: high-resolution crystal structure of a ribonuclease A complex with a potent 3',5'-pyrophosphate-linked dinucleotide inhibitor.

Biochemistry 38 10287-97 (1999)
Cited: 31 times
EuropePMC logo PMID: 10441122

Abstract

The crystal structure of ribonuclease A (RNase A) in complex with pdUppA-3'-p [5'-phospho-2'-deoxyuridine-3'-pyrophosphate (P'-->5') adenosine 3'-phosphate] has been determined at 1.7 A resolution. This dinucleotide is the most potent low molecular weight inhibitor of RNase A reported to date (K(i) = 27 nM) and is also effective against two major nonpancreatic RNases: eosinophil-derived neurotoxin and RNase-4; in all cases, tight binding in large part derives from the unusual 3',5'-pyrophosphate internucleotide linkage [Russo, N., and Shapiro, R. (1999) J. Biol. Chem. 274, 14902-14908]. The design of pdUppA-3'-p was based on the crystal structure of RNase A complexed with 5'-diphosphoadenosine 3'-phosphate (ppA-3'-p) [Leonidas, D. D., Shapiro, R., Irons, L. I., Russo, N., and Acharya, K. R. (1997) Biochemistry 36, 5578-5588]. The adenosine of pdUppA-3'-p adopts an atypical syn conformation not observed for standard adenosine nucleotides bound to RNase A. This conformation, which allows extensive interactions with Asn 67, Gln 69, Asn 71, and His 119, is associated with the placement of the 5'-beta-phosphate of the adenylate, rather than alpha-phosphate, at the site where substrate phosphodiester bond cleavage occurs. The contacts of the deoxyuridine 5'-phosphate portion of pdUppA-3'-p appear to be responsible for the 9-fold increased affinity of this compound as compared to ppA-3'-p: the uracil base binds to Thr 45 in the same manner as previous pyrimidine inhibitors, and the terminal 5'-phosphate is positioned to form medium-range Coulombic interactions with Lys 66. The full potential benefit of these added interactions is not realized because of compensatory losses of hydrogen bonds of Lys 7 and Gln 11 with the terminal 3'-phosphate and the adenylate 5'-alpha-phosphate, which were not predicted by modeling. The results reported here have important implications for the design of improved inhibitors of RNase A and for the development of therapeutic agents to control the activities of RNase homologues such as eosinophil-derived neurotoxin and angiogenin that have roles in human pathologies.

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Articles - 1qhc mentioned but not cited (13)



Articles citing this publication (17)

  1. Reversible substrate-induced domain motions in ribonuclease A. Vitagliano L, Merlino A, Zagari A, Mazzarella L. Proteins 46 97-104 (2002)
  2. High-resolution crystal structures of ribonuclease A complexed with adenylic and uridylic nucleotide inhibitors. Implications for structure-based design of ribonucleolytic inhibitors. Leonidas DD, Chavali GB, Oikonomakos NG, Chrysina ED, Kosmopoulou MN, Vlassi M, Frankling C, Acharya KR. Protein Sci 12 2559-2574 (2003)
  3. The binding of 3'-N-piperidine-4-carboxyl-3'-deoxy-ara-uridine to ribonuclease A in the crystal. Leonidas DD, Maiti TK, Samanta A, Dasgupta S, Pathak T, Zographos SE, Oikonomakos NG. Bioorg Med Chem 14 6055-6064 (2006)
  4. Structural and mechanistic basis for preferential deadenylation of U6 snRNA by Usb1. Nomura Y, Roston D, Montemayor EJ, Cui Q, Butcher SE. Nucleic Acids Res 46 11488-11501 (2018)
  5. Binding of non-natural 3'-nucleotides to ribonuclease A. Jenkins CL, Thiyagarajan N, Sweeney RY, Guy MP, Kelemen BR, Acharya KR, Raines RT. FEBS J 272 744-755 (2005)
  6. Inhibition of mammalian ribonucleases by endogenous adenosine dinucleotides. Kumar K, Jenkins JL, Jardine AM, Shapiro R. Biochem Biophys Res Commun 300 81-86 (2003)
  7. Nucleoside Tetra- and Pentaphosphates Prepared Using a Tetraphosphorylation Reagent Are Potent Inhibitors of Ribonuclease A. Shepard SM, Windsor IW, Raines RT, Cummins CC. J Am Chem Soc 141 18400-18404 (2019)
  8. Selective cleavage of ncRNA and antiviral activity by RNase2/EDN in THP1-induced macrophages. Lu L, Li J, Wei R, Guidi I, Cozzuto L, Ponomarenko J, Prats-Ejarque G, Boix E. Cell Mol Life Sci 79 209 (2022)
  9. 3'-Oxo-, amino-, thio- and sulfone-acetic acid modified thymidines: effect of increased acidity on ribonuclease A inhibition. Datta D, Samanta A, Dasgupta S, Pathak T. Bioorg Med Chem 21 4634-4645 (2013)
  10. The binding of IMP to ribonuclease A. Hatzopoulos GN, Leonidas DD, Kardakaris R, Kobe J, Oikonomakos NG. FEBS J 272 3988-4001 (2005)
  11. Functional and structural analyses of N-acylsulfonamide-linked dinucleoside inhibitors of RNase A. Thiyagarajan N, Smith BD, Raines RT, Acharya KR. FEBS J 278 541-549 (2011)
  12. Dinucleosides with non-natural backbones: a new class of ribonuclease A and angiogenin inhibitors. Debnath J, Dasgupta S, Pathak T. Chemistry 18 1618-1627 (2012)
  13. Crystallographic and functional studies of a modified form of eosinophil-derived neurotoxin (EDN) with novel biological activities. Chang C, Newton DL, Rybak SM, Wlodawer A. J Mol Biol 317 119-130 (2002)
  14. Ribonuclease A inhibition by carboxymethylsulfonyl-modified xylo- and arabinopyrimidines. Datta D, Dasgupta S, Pathak T. ChemMedChem 9 2138-2149 (2014)
  15. Heterogeneous Pyrophosphate-Linked DNA-Oligonucleotides: Aversion to DNA but Affinity for RNA. Anderson BA, Krishnamurthy R. Chemistry 24 6837-6842 (2018)
  16. Carboxylated acyclonucleosides: synthesis and RNase A inhibition. Chakraborty K, Dasgupta S, Pathak T. Molecules 20 5924-5941 (2015)
  17. Sulfonic nucleic acids (SNAs): a new class of substrate mimics for ribonuclease A inhibition. Datta D, Dasgupta S, Pathak T. Org Biomol Chem 17 7215-7221 (2019)


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