Online Supporting Information S1 The benchmark dataset for the drug-target enzyme interaction system. It contains 8,157 genedrug pair samples, of which 2,719 are positive and 5,438 negative. The 1st column of the table indicates the nature of samples with 1 for positive and 2 for negative; the 2nd column shows the code of target gene; and the 3rd column shows the code of drug. All the detailed information for the genes and drugs listed here can be found in  An intermolecular RNA triplex provides insight into structural determinants for the pseudoknot stimulator of −1 ribosomal frameshifting An efficient −1 programmed ribosomal frameshifting (PRF) signal requires an RNA slippery sequence and a downstream RNA stimulator, and the hairpin-type pseudoknot is the most common stimulator. However, a pseudoknot is not sufficient to promote −1 PRF. hTPK-DU177, a pseudoknot derived from human telomerase RNA, shares structural similarities with several −1 PRF pseudoknots and is used to dissect the roles of distinct structural features in the stimulator of −1 PRF. Structure-based mutagenesis on hTPK-DU177 reveals that the −1 PRF efficiency of this stimulator can be modulated by sequential removal of base–triple interactions surrounding the helical junction. Further analysis of the junction-flanking base triples indicates that specific stem–loop interactions and their relative positions to the helical junction play crucial roles for the −1 PRF activity of this pseudoknot. Intriguingly, a bimolecular pseudoknot approach based on hTPK-DU177 reveals that continuing triplex structure spanning the helical junction, lacking one of the loop-closure features embedded in pseudoknot topology, can stimulate −1 PRF. Therefore, the triplex structure is an essential determinant for the DU177 pseudoknot to stimulate −1 PRF. Furthermore, it suggests that −1 PRF, induced by an in-trans RNA via specific base–triple interactions with messenger RNAs, can be a plausible regulatory function for non-coding RNAs. During translation, the ribosomes have to maintain correct reading frame to faithfully decode the in-frame messenger RNA (mRNA) sequences into ordered amino acid sequences. However, specific information within mRNAs can trigger the slippage of reading frames for elongating ribosomes, and thus lead to the frameshifting events (1) . In one case, the ribosomes are induced to move backward one base in the 5 0 direction in response to specific signals within mRNAs, and then continue translation in the new À1 reading frame (2) . Such a À1 programmed ribosomal frameshifting (PRF) is adopted by a variety of viruses to maintain a specific ratio between structural and enzymatic proteins (3) (4) (5) (6) (7) , and examples of À1 PRF in cellular genes are also reported (8) (9) (10) . The mechanism for the induction of À1 PRF by a stimulator is a delicate process and may involve multiple factors. Efficient eukaryotic À1 PRF requires two in cis RNA elements within the mRNA (11, 12) : a heptanucleotide slippery site of XXXYYYZ sequences, where the frameshift occurs, and a downstream RNA structure connected by a spacer. The optimal distance between stimulator and slippery site, separated by the spacer, will then position the A-and P-site tRNAs on the slippery site (13) (14) (15) . With the sequence feature of X being any three identical nucleotides, Y being either AAA or UUU, and Z not being a G, these cooperative RNA elements can increase the probability of a ribosome to slip with A-and P-site tRNAs in the 5 0 direction by one base along the mRNA (from X XXY YYZ to XXX YYY Z) (15) .