3o2f
Structure of the N-domain of GRP94 bound to the HSP90 inhibitor PU-H54Structure of the N-domain of GRP94 bound to the HSP90 inhibitor PU-H54
Structural highlights
Function[ENPL_CANFA] Molecular chaperone that functions in the processing and transport of secreted proteins. When associated with CNPY3, required for proper folding of Toll-like receptors. Functions in endoplasmic reticulum associated degradation (ERAD). Has ATPase activity (By similarity). Publication Abstract from PubMedAlthough the Hsp90 chaperone family, comprised in humans of four paralogs, Hsp90alpha, Hsp90beta, Grp94 and Trap-1, has important roles in malignancy, the contribution of each paralog to the cancer phenotype is poorly understood. This is in large part because reagents to study paralog-specific functions in cancer cells have been unavailable. Here we combine compound library screening with structural and computational analyses to identify purine-based chemical tools that are specific for Hsp90 paralogs. We show that Grp94 selectivity is due to the insertion of these compounds into a new allosteric pocket. We use these tools to demonstrate that cancer cells use individual Hsp90 paralogs to regulate a client protein in a tumor-specific manner and in response to proteome alterations. Finally, we provide new mechanistic evidence explaining why selective Grp94 inhibition is particularly efficacious in certain breast cancers. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2.,Patel PD, Yan P, Seidler PM, Patel HJ, Sun W, Yang C, Que NS, Taldone T, Finotti P, Stephani RA, Gewirth DT, Chiosis G Nat Chem Biol. 2013 Sep 1. doi: 10.1038/nchembio.1335. PMID:23995768[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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