5mks
From Proteopedia
HSP72-NBD bound to compound TCI 8 - Tyr15 in down-conformation
Structural highlights
Function[HS71A_HUMAN] In cooperation with other chaperones, Hsp70s stabilize preexistent proteins against aggregation and mediate the folding of newly translated polypeptides in the cytosol as well as within organelles. These chaperones participate in all these processes through their ability to recognize nonnative conformations of other proteins. They bind extended peptide segments with a net hydrophobic character exposed by polypeptides during translation and membrane translocation, or following stress-induced damage. In case of rotavirus A infection, serves as a post-attachment receptor for the virus to facilitate entry into the cell. Essential for STUB1-mediated ubiquitination and degradation of FOXP3 in regulatory T-cells (Treg) during inflammation (PubMed:23973223).[1] [2] [3] Publication Abstract from PubMedThe stress-inducible molecular chaperone, HSP72, is an important therapeutic target in oncology, but inhibiting this protein with small molecules has proven particularly challenging. Validating HSP72 inhibitors in cells is difficult owing to competition with the high affinity and abundance of its endogenous nucleotide substrates. We hypothesized this could be overcome using a cysteine-targeted irreversible inhibitor. Using rational design, we adapted a validated 8-N-benzyladenosine ligand for covalent bond formation and confirmed targeted irreversible inhibition. However, no cysteine in the protein was modified; instead, we demonstrate that lysine-56 is the key nucleophilic residue. Targeting this lysine could lead to a new design paradigm for HSP72 chemical probes and drugs. An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56.,Pettinger J, Le Bihan YV, Widya M, van Montfort RL, Jones K, Cheeseman MD Angew Chem Int Ed Engl. 2017 Feb 22. doi: 10.1002/anie.201611907. PMID:28225177[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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