5h5r
Crystal structure of human GPX4 in complex with GXpep-2Crystal structure of human GPX4 in complex with GXpep-2
Structural highlights
FunctionGPX4_HUMAN Protects cells against membrane lipid peroxidation and cell death. Required for normal sperm development and male fertility. Could play a major role in protecting mammals from the toxicity of ingested lipid hydroperoxides. Essential for embryonic development. Protects from radiation and oxidative damage (By similarity). Publication Abstract from PubMedThe phospholipid hydroperoxidase glutathione peroxidase (GPX4) is an enzyme that reduces lipid hydroperoxides in lipid membranes. Recently, GPX4 has been investigated as a target molecule that induces iron-dependent cell death (ferroptosis) selectively in cancer cells that express mutant Ras. GPX4 inhibitors have the potential to become novel anti-cancer drugs. However, there are no druggable pockets for conventional small molecules on the molecular surface of GPX4. To generate GPX4 inhibitors, we examined the use of peptides as an alternative to small molecules. By screening peptide libraries displayed on T7 phages, and analyzing the X-ray crystal structures of the peptides, we successfully identified one peptide that binds to near Sec73 of catalytic site and two peptides that bind to another site on GPX4. To our knowledge, this is the first study reporting GPX4 inhibitory peptides and their structural information. Discovery of GPX4 inhibitory peptides from random peptide T7 phage display and subsequent structural analysis.,Sakamoto K, Sogabe S, Kamada Y, Matsumoto SI, Kadotani A, Sakamoto JI, Tani A Biochem Biophys Res Commun. 2016 Nov 9. pii: S0006-291X(16)31890-3. doi:, 10.1016/j.bbrc.2016.11.035. PMID:27836545[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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