9c0y
Clathrin terminal domain complexed with Pitstop 2c
Structural highlights
DiseaseCLH1_HUMAN Translocation renal cell carcinoma;Inflammatory myofibroblastic tumor. FunctionCLH1_HUMAN Clathrin is the major protein of the polyhedral coat of coated pits and vesicles. Two different adapter protein complexes link the clathrin lattice either to the plasma membrane or to the trans-Golgi network. Publication Abstract from PubMedClathrin-mediated endocytosis (CME) is the predominant endocytic pathway in eukaryotic cells and a major regulator of cell physiology as it facilitates the internalization of receptors, channels, and transporters and viral entry. The clathrin terminal domain acts as a central protein interaction hub within the endocytic protein network. Previously described inhibitors of CME display off-target activities that result in cytotoxicity, providing limitations to their use. We report the development and characterization of next-generation small molecule inhibitors of clathrin terminal domain function. These compounds termed Pitstop 2c and Pitstop 2d occupy the binding site within the clathrin terminal domain for endocytic protein ligands including epsin, resulting in potent inhibition of receptor-mediated endocytosis and reduced entry of vesicular stomatitis virus (VSV) with minimal cytotoxic side effects. Next-generation Pitstops thus provide an improved toolset to address clathrin function in cell physiology with potential applications as inhibitors of virus and pathogen entry. Next-generation small molecule inhibitors of clathrin function acutely inhibit endocytosis.,Horatscheck A, Krauss M, Bulut H, Chambon V, Zadah MS, Dransart E, Peloza K, Santos KF, Robertson MJ, Prichard K, Miksche S, Radetzki S, von Kries JP, Wahl MC, McCluskey A, Johannes L, Haucke V, Nazare M Structure. 2025 Mar 7:S0969-2126(25)00064-4. doi: 10.1016/j.str.2025.02.011. PMID:40112806[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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