2xzg
Clathrin Terminal Domain Complexed with Pitstop 1
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) regulates many cell physiological processes such as the internalization of growth factors and receptors, entry of pathogens, and synaptic transmission. Within the endocytic network, clathrin functions as a central organizing platform for coated pit assembly and dissociation via its terminal domain (TD). We report the design and synthesis of two compounds named pitstops that selectively block endocytic ligand association with the clathrin TD as confirmed by X-ray crystallography. Pitstop-induced inhibition of clathrin TD function acutely interferes with receptor-mediated endocytosis, entry of HIV, and synaptic vesicle recycling. Endocytosis inhibition is caused by a dramatic increase in the lifetimes of clathrin coat components, including FCHo, clathrin, and dynamin, suggesting that the clathrin TD regulates coated pit dynamics. Pitstops provide new tools to address clathrin function in cell physiology with potential applications as inhibitors of virus and pathogen entry and as modulators of cell signaling. Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition.,von Kleist L, Stahlschmidt W, Bulut H, Gromova K, Puchkov D, Robertson MJ, Macgregor KA, Tomlin N, Pechstein A, Chau N, Chircop M, Sakoff J, von Kries JP, Saenger W, Krausslich HG, Shupliakov O, Robinson PJ, McCluskey A, Haucke V Cell. 2011 Aug 5;146(3):471-84. PMID:21816279[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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