of Yoda1, a small molecule Piezo1 activator, and identify stretch-induced conformational rearrangements of the blades. Yoda1 binding uncouples two adjacent Piezo repeats, facilitating stretch-induced blade motions, and alters long-range residue-residue contacts between pore and blades, as evidenced by Yoda1-induced channel activation of a mechanically-insensitive mutant. In addition, cation-selective fenestrations allow potassium, not chloride, ions to enter a pore vestibule. Our work reveals the structural bases of cationic selectivity, chemical modulation and mechanical sensing in a mammalian Piezo channel.
It has almost been 40 years since the Ras proteins were discovered as the first human oncogenes. They remain among the most important genes for regulating mammalian cell growth and are involved in more than a quarter of human cancers. Out of 167 members of the Ras superfamily, K-Ras mutations are the most abundant in human cancers. Particularly, the K-Ras G12C mutations are known to be involved in pancreatic, colon and lung cancers as well as leukemias. Though progress has been made, approaches that target Ras proteins for therapeutic purposes still remain challenging. In fact, no drugs treating Ras-related cancers are currently on the market. However, there is now renewed interest in the Ras area and newer approaches have highlighted the targeting of several types of tumors and treating cancer patients. In this review, we will summarize recent K-Ras drug candidates and approaches in the pre-clinical, clinical and post clinical pipelines that show promise for targeting and reducing Ras-related tumors. Macromolecules such as mRNA vaccines, siRNA, and T-cell receptors that target Ras will also be discussed. The newer molecules and the recent approaches to be discussed suggest that the “undruggable” era of Ras proteins could be coming to an end.
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