Conformational restriction nucleotides

D Rigidified ribose in nucleotide construction E Conformationally restricted tetrahydro- 237... 

Extensive synthetic efforts have been made into the preparation of highly complex nucleosidic building blocks, whereby functionalization and conformational restriction were introduced via multiple ring incorporation into the glycosidic framework of the nucleotides. The introduction of such complexity has come at a price as these compounds often require lengthy synthetic sequences to achieve both chemoselectivity and stereochemical definition. 

Fig. 5.19. GTP and GDP structures of transducin. The Ga,t subunit of transducin possesses—in contrast to Ras protein and to other small regulatory GTPases —an a-hehcal domain that hides and closes the G-nucleotide binding pocket. The conformational changes that accompany the transition from the inactive G t GDP form (a) into the active G t GTP form (b), are restricted to three structural sections that are known as switches I, II and III. Switch I includes the link of the a-helical domain with P2, switch II affects in particular hehx a2, and switch III, the pS—a3 loop. Switch III includes a sequence that is characteristic for the a-subunits of the heterotrimeric G-proteins. The conformational changes of switches II and III affect structural sections that are assumed to be binding sites for the effector molecule adenylyl cyclase (AC) and the y-subunit of cGMP-dependent phosphodiesterase (PDEy), based on mutation experiments and biochemical investigations. MOLSKRIPT representation according to Krauhs, (1991).

S Additional information <2, 4> (<4> formation of a ternary complex, addition of substrates is random [5] <2> ATP-mediated induced-fit of LID in CMPKcoli modulated by CMP leading to a closed conformation of the active site, protected from water [15] <4> the UMP-CMP kinase has a relaxed enantiospecificity for the nucleoside monophosphate acceptor site, but it is restricted to D-nucleotides at the donor site [26]) [5, 15, 26]... 

Structural variation in DNA reflects three things the different possible conformations of the deoxyribose, rotation about the contiguous bonds that make up the phosphodeoxyribose backbone (Fig. 8-18a), and free rotation about the C-l -N-glycosyl bond (Fig. 8-18b). Because of steric constraints, purines in purine nucleotides are restricted to two stable conformations with respect to deoxyribose, called syn and anti (Fig. 8-18b). Pyrimidines are generally restricted to the anti conformation because of steric interference between the sugar and the carbonyl oxygen at C-2 of the pyrimidine. 

Conformational analysis of silicon analogues of cyclic phosphates, such as (5) and (6), reveal that they have restricted conformations analogous to those observed for 3, 5 -cyclic nucleotides <90CL97>. The pseudorotation angle (P) obtained for compound (5) is 43.4°. This indicates that the twist conformation 4T3 is in good agreement with the mean value (45°) obtained for 3/,5/-cyclic nucleotides. 

Nucleosides and Nucleotides occur in a limited number of preferred conformations. Except for the planar purine or pyrimidine base, the nucleotide component of the nucleic acids contains only single bonds (see Fig. 17.1). Rotation about bonds is restrained by the requirements of the furanose ring closure, and for the acyclic bonds, rotation is restricted by electronic factors and is limited by intramolecular interactions. Therefore only a few conformations have to be considered if nucleosides and nucleotides are described in their three-dimensional shapes. 

Koizumi, M. (2007). True antisense oligonucleotides with modified nucleotides restricted in the N-conformation. Curr Top Med Chem 7, 661-665. 

---