Structure of a general nuclease-resistant ribozyme bound to a generic target RNA. The ribozyme consists primarily of 2′-O-Me nucleotides (lower case). The 3′ and 5′ ends are protected by an inverted 3′-3′ deoxyabasic sugar (iB) and four phosphorothioate linkages (s), respectively. The five purine nucleotides (rA or rG) in the catalytic core (shown in green) are required for catalytic activity. A single non-natural carbon containing pyrimidine analog (2′-C-allyluridine) at U4 was used to stabilize the core and maintain activity. The ribozyme binds its cognate target via Watson-Crick base-pairing. In the target strand, cleavage takes place 3′ to the unpaired nucleotide H (H = A, C, or U). This type of ribozyme has an ex vivo serum t_1/2 = 10 days.