In Nature this week, Stanford University scientists led by 2012 Nobel Laureate Brian Kobilka publish the structure of a human G-protein-coupled receptor bound to a drug. Specifically, they showed the crystal structure of the coagulation-mediating human protease-activated receptor 1 associated with vorapaxar, a PAR1 antagonist under clinical development for the prevention of cardiovascular events in patients with a history of heart attacks. "The structure reveals an unusual mode of drug binding that explains how a small molecule binds virtually irreversibly to inhibit receptor activation by the tethered ligand of PAR1," and is expected to help in the development of next-generation PAR1 antagonists.
Meanwhile, in Nature Biotechnology, a multi-institute team led by researchers from the Broad Institute present a new algorithm aimed at addressing the variability and statistical challenges facing differential analysis of gene and transcript expression using high-throughput RNA sequencing. The algorithm, called Cuffdiff 2, estimates expression at transcript-level resolution and controls for variability evident across replicate libraries and "robustly identifies differentially expressed transcripts and genes and reveals differential splicing and promoter-preference changes." The researchers say that the algorithm will enable improved analysis of complex cellular circuitry and allow for the precise association of genomic sequence to gene regulation.