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991.
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Steroidal bivalent ligands for the estrogen receptor: Design,synthesis, characterization and binding affinities 总被引:1,自引:0,他引:1
Andrew L. LaFrate Kathryn E. Carlson John A. Katzenellenbogen 《Bioorganic & medicinal chemistry》2009,17(10):3528-3535
Steroidal bivalent ligands for the estrogen receptor (ER) were designed using crystal structures of ERα dimers as a template. The syntheses of several 17α-ethynylestradiol-based bivalent ligands with varying linker compositions and lengths are described. The binding affinities of these bivalent ligands for ERα and ERβ were determined. In the two series of bivalent ligands that we synthesized, there is a clear correlation between linker length and binding affinity, both of which reach a maximum at the same tether length. Further studies are underway to explore aspects of bivalent ligand and control compound binding to the ERs and their effects on ER dimer formation; these results will be reported in a subsequent publication. 相似文献
993.
Byung Seok Moon Kathryn E. Carlson John A. Katzenellenbogen Tae Hyun Choi Dae Yoon Chi Jung Young Kim Gi Jeong Cheon Hun Yeong Koh Kyo Chul Lee Gwangil An 《Bioorganic & medicinal chemistry》2009,17(9):3479-3488
We have investigated halogen-substituted non-steroidal estrogens with selective binding affinity for the estrogen receptor β (ERβ that might be used for imaging the levels of this ER-subtype in breast tumors by positron emission tomography (PET). Based on diarylpropionitrile (DPN, 1a), a compound previously reported that has a 72-fold binding selectivity for ERβ, we developed a series of DPN analogs having methyl-, hydroxyl-, and halogen substituents, including fluoroethyl and fluoropropyl groups. In competitive radiometric binding assays with [3H]estradiol, all of these DPN analogs showed high ERβ/ERα selectivity; while the selectivity varied, in some cases it reached nearly 300-fold (RBA: ERα, 0.023%; ERβ, 6.25%). The absolute ERβ binding affinities, however, were not sufficient to merit further consideration for developing these ligands as PET imaging agents. 相似文献
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Steven T. Truschel Sabrina Simoes Subba Rao Gangi Setty Dawn C. Harper Danièle Tenza Penelope C. Thomas Kathryn E. Herman Sara D. Sackett David C. Cowan Alexander C. Theos Graça Raposo Michael S. Marks 《Traffic (Copenhagen, Denmark)》2009,10(9):1318-1336
Melanosomes are lysosome-related organelles that coexist with lysosomes within melanocytes. The pathways by which melanosomal proteins are diverted from endocytic organelles toward melanosomes are incompletely defined. In melanocytes from mouse models of Hermansky-Pudlak syndrome that lack BLOC-1, melanosomal proteins such as tyrosinase-related protein 1 (Tyrp1) accumulate in early endosomes. Whether this accumulation represents an anomalous pathway or an arrested normal intermediate in melanosome protein trafficking is not clear. Here, we show that early endosomes are requisite intermediates in the trafficking of Tyrp1 from the Golgi to late stage melanosomes in normal melanocytic cells. Kinetic analyses show that very little newly synthesized Tyrp1 traverses the cell surface and that internalized Tyrp1 is inefficiently sorted to melanosomes. Nevertheless, nearly all Tyrp1 traverse early endosomes since it becomes trapped within enlarged, modified endosomes upon overexpression of Hrs. Although Tyrp1 localization is not affected by Hrs depletion, depletion of the ESCRT-I component, Tsg101, or inhibition of ESCRT function by dominant-negative approaches results in a dramatic redistribution of Tyrp1 to aberrant endosomal membranes that are largely distinct from those harboring traditional ESCRT-dependent, ubiquitylated cargoes such as MART-1. The lysosomal protein content of some of these membranes and the lack of Tyrp1 recycling to the plasma membrane in Tsg101-depleted cells suggests that ESCRT-I functions downstream of BLOC-1. Our data delineate a novel pathway for Tyrp1 trafficking and illustrate a requirement for ESCRT-I function in controlling protein sorting from vacuolar endosomes to the limiting membrane of a lysosome-related organelle. 相似文献
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Kathryn B. Garber 《American journal of human genetics》2009,84(3):305-306
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Mingzhi Xu Kathryn C.B. Tan Renyong Guo Ying Wong 《Biochemical and biophysical research communications》2009,390(4):1349-390