Structural highlights
7zkr is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
|
| Method: | X-ray diffraction, Resolution 1.1Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
GBRAP_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 PubMed
The 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
- ↑ Lee JH, Rho SB, Chun T. GABAA receptor-associated protein (GABARAP) induces apoptosis by interacting with DEAD (Asp-Glu-Ala-Asp/His) box polypeptide 47 (DDX 47). Biotechnol Lett. 2005 May;27(9):623-8. PMID:15977068 doi:http://dx.doi.org/10.1007/s10529-005-3628-2
- ↑ 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. Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy. J Am Chem Soc. 2022 Aug 17;144(32):14687-14697. doi: 10.1021/jacs.2c04699. Epub, 2022 Aug 2. PMID:35917476 doi:http://dx.doi.org/10.1021/jacs.2c04699
