PROMISING PAIRS: An NMR screen for inhibitors of the cell cycle regulator p27Kip1 yielded a number of hits, which clustered into two groups that bind to different parts of the protein. Here are representative small molecules that bind to the two different regions. The colors of the polygons reflect the binding site characteristics favored by inhibitors (blue, electropositive; red, electronegative; gold, hydrophobic; yellow, van der Waal) and the polygons’ sizes indicate the favorability of the contact interaction.SCI REP, 5:15686, 2015
Scientists know a lot about drugs for proteins that settle down into nice, stable conformations and stick with them. Not so for the set known as intrinsically disordered proteins, or IDPs. Their amino acid chains rapidly cycle between multiple conformations, sometimes within microseconds. They’re continually striking different poses, like a nanoscopic, superspeed version of Madonna in her music video “Vogue.”
As many as one-third to one-half of human proteins are partially or fully disordered, and those proteins are common in signaling and disease pathways. Normally tightly regulated, IDPs are multitasking molecules that can be swiftly repurposed and reconfigured to play roles in multiple regulatory cascades. But when their expression is altered, IDPs can be implicated in conditions such as cancer, cardiovascular disease, and neurodegeneration. Their ...
