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Human GABARAP in complex with stapled peptide Pen8-orthoHuman GABARAP in complex with stapled peptide Pen8-ortho
Structural highlights
FunctionGBRAP_HUMAN May play a role in intracellular transport of GABA(A) receptors and its interaction with the cytoskeleton. Involved in apoptosis. Involved in autophagy (By similarity).[1] Publication Abstract from PubMedThe LC3/GABARAP family of proteins is involved in nearly every stage of autophagy. Inhibition of LC3/GABARAP proteins is a promising approach to blocking autophagy, which sensitizes advanced cancers to DNA-damaging chemotherapy. Here, we report the structure-based design of stapled peptides that inhibit GABARAP with nanomolar affinities. Small changes in staple structure produced stapled peptides with very different binding modes and functional differences in LC3/GABARAP paralog selectivity, ranging from highly GABARAP-specific to broad inhibition of both subfamilies. The stapled peptides exhibited considerable cytosolic penetration and resistance to biological degradation. They also reduced autophagic flux in cultured ovarian cancer cells and sensitized ovarian cancer cells to cisplatin. These small, potent stapled peptides represent promising autophagy-modulating compounds that can be developed as novel cancer therapeutics and novel mediators of targeted protein degradation. Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy.,Brown H, Chung M, Uffing A, Batistatou N, Tsang T, Doskocil S, Mao W, Willbold D, Bast RC Jr, Lu Z, Weiergraber OH, Kritzer JA J Am Chem Soc. 2022 Aug 17;144(32):14687-14697. doi: 10.1021/jacs.2c04699. Epub, 2022 Aug 2. PMID:35917476[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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