Nucleosides binding sites

La Regina, G., Coluccia, A., Di Pasquali, A., Silvestri, R. Docking and 3D QSAR Studies on Indolyl Aryl Sulfones. Binding Mode Exploration at the HIV-1 Reverse Transcriptase Non-nucleoside Binding Site and Design of Highly Active N-(2-Hydroxyethyl)carboxamide and N-(2-Hydroxyethyl)carbohydrazide Derivatives./. Med. Chem. 2005, 48, 213-23. 

Black, M. E., and Loeb, L. A. (1993). Identification of important residues within the putative nucleoside binding site of HSV-1 thymidine kinase by random sequence selection analysis of selected mutants in vitro. Biochemistry, 32, 11618—11626. 

The recent determination of the crystal structure of a ternary catalytic complex of HW-1 RT with a substrate (dTTP) and the DNA-primer and template [121] (Fig. 8) has provided the structured basis of resistance it has been found that most mutations causing resistemce to nucleoside-analog drugs are located closely to the nucleoside binding site. 

Figure 9 HSV-1 TK nucleoside binding site (left) and (right) quantum-meehanical model used in the calculations. (Reproduced with permission from ref. [133], Copjnight 1998 Wiley.)...

Visser F, Zhang J, Raborn RT et al. Residue 33 of human equilibrative nucleoside transporter 2 is a functionally important component of both the dipyridamole and nucleoside binding sites. Mol Pharmacol 2005 67(4) 1291-1298. 

Rejman et al. reported the N-phosphonocarbonylpyrrolidine derivatives of guanine (67). These compounds can act as bisubstrate inhibitors that occupy both the phosphate and nucleoside binding sites of human purine nucleoside phosphorylase. 

Kukolj G, McGibbon GA, McKercher G, Marquis M, Lefebvre S, Thauvette L, Gauthier J, Goulet S, Poupait MA, Beaulieu PL (2005) Binding site characterization and resistance to a class of non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase, J Biol Chem 280 39260-39267... 

Viswanadhan VN, Ghose AK and Weinstein JN. Mapping the binding site of the nucleoside transporter protein a 3D-OSAR study. Biochim Biophys Acta 1990 1039 356-66. 

Synthetic nonhydrolyzable analogs of nucleoside triphosphates (Figure 33-13) allow investigators to distinguish the effects of nucleotides due to phosphoryl transfer from effects mediated by occupancy of allosteric nucleotide-binding sites on regulated enzymes. 

Attention has been drawn to the potential of phosphoric acid anhydrides of nucleoside 5 -carboxylic acids (14) as specific reagents for investigating the binding sites of enzymes. For example, (14 B = adenosine) inactivates adenylosuccinate lyase from E. coli almost completely, but has little effect on rabbit muscle AMP deaminase. The rate of hydrolysis of (14) is considerably faster than that of acetyl phosphate, suggesting intramolecular assistance by the 3 -hydroxyl group or the 3-nitrogen atom. 

VI. REVERSE TRANSCRIPTASE INHIBITORS INTERACTING WITH A NONSUBSTRATE BINDING SITE NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS... 

Unlike the other alkaline earth and transition metal ions, essentially on account of its small ionic radius and consequent high electron density, Mg2+ tends to bind the smaller water molecules rather than bulkier ligands in the inner coordination sphere. Many Mg2+-binding sites in proteins have only 3, 4 or even less direct binding contacts to the protein, leaving several sites in the inner coordination sphere occupied by water, or in the phosphoryl transferases, by nucleoside di- or triphosphates. 

The NNRTIs bind directly to HIV-1 reverse transcriptase (Figure 49-4), resulting in allosteric inhibition of RNA- and DNA-dependent DNA polymerase. The binding site of NNRTTs is near to but distinct from that of NRTTs. Unlike the NRTT agents, NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active. 

C NMR spectroscopy is also suitable for determining the binding sites of metal ions in nucleosides and nucleotides Thus, one concluded from 13C NMR studies on guanosine in the presence of metal ions that hard metal ions bind to 0-6 and soft metal ions to N-l after its deprotonation [754],... 

Reich and his colleagues 443) have found that poly F is an excellent substrate for RNase and also that the nucleosides in the polymer have the unusual syn conformation. In contrast to Ikehara et al. 441), these authors found no evidence for the hydrolysis of F > p where the rate of degradation of poly F to give F > p was about equal to that on poly C to give C > p. The demonstration of the syn conformation was critical for an understanding of these data. The nucleoside can fit the pyrimidine binding site when in the syn conformation as discussed in more detail below. 

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