Research into the role of plasma proteins on the human disease phenome is reported in Nature Genetics this week. Plasma proteins are known to be involved in a range of biological functions and have become a major source of druggable targets. To further investigate, a team led by scientists from the University of Bristol used Mendelian randomization (MR) and colocalization to estimate the effects of 1,002 proteins on 225 phenotypes, including 153 diseases and 72 risk factors. Among their findings are 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes, and an evaluation of historic drug-development programs reveals that target-indication pairs with MR and colocalization support were more likely to result in regulatory approval. "Our study provides both an analytical framework and an open resource to prioritize potential new targets and a valuable resource for evaluation of both efficacy and repurposing opportunities by phenome-wide evaluation of on-target association," the researchers write.
The high-resolution crystal structures of the Cas9 nuclease from Streptococcus thermophilus (St1Cas9), in complex with single-guide RNA (sgRNA) and double-stranded DNA (dsRNA) that contains one of three different protospacer adjacent motifs (PAMs), is presented in Nature Catalysis this week. St1Cas9 is one of multiple Cas9 orthologs from distinct bacterial species that are being used for CRISPR genome editing in living cells and it has shown several advantages over the widely used Streptococcus pyogenes Cas9. To better understand its properties, investigators from ShanghaiTech University systematically characterized St1Cas9 through determining multiple crystal structures of the St1Cas9-sgRNA-dsDNA complex. "Interestingly, all of the structures represent an HNH catalytic state that has rarely been observed in the previous Cas9 crystal structures, clearly depicting the active enzyme conformation," they write. They uncover a unique wing region in the REC domain that forms intensive interactions with the HNH domain, playing a key role in regulating St1Cas9 DNA cleavage activity and likely stabilizing the active conformation, and find that St1Cas9 uses a chemistry for PAM recognition that is distinct from that of other Cas9 orthologs.