5AGX

Bcl-2 alpha beta-1 LINEAR complex

Summary for 5AGX

• Entry DOI: 10.2210/pdb5agx/pdb
• Related: 5AGW
• Descriptor: APOPTOSIS REGULATOR BCL-2, BCL-2-LIKE PROTEIN 1, APOPTOSIS REGULATOR BCL-2, BCL-2-LIKE PROTEIN 11, ... (4 entities in total)
• Functional Keywords: foldamer, bim, apoptosis
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Mitochondrion outer membrane ; Single-pass membrane protein : P10415 Q07817; Endomembrane system ; Peripheral membrane protein . Isoform BimEL: Mitochondrion. Isoform BimL: Mitochondrion. Isoform BimS: Mitochondrion. Isoform Bim-alpha1: Mitochondrion: P10415
• Total number of polymer chains: 4
• Total formula weight: 44137.49

Authors

Smith, B.J.,F Lee, E.,Checco, J.W.,Gellman, S.H.,Fairlie, W.D. (deposition date: 2015-02-04, release date: 2015-09-09, Last modification date: 2024-05-01)

Primary citation

Checco, J.W.,Lee, E.F.,Evangelista, M.,Sleebs, N.,Rodgers, K.,Pettikiriarachchi, A.,Kershaw, N.,Eddinger, G.A.,Belair, D.G.,Wilson, J.L.,Eller, C.H.,Raines, R.T.,Murphy, W.L.,Smith, B.J.,Gellman, S.H.,Fairlie, W.D.
Alpha Beta Peptide Foldamers Targeting Intracellular Protein-Protein Interactions with Activity on Living Cells
J.Am.Chem.Soc., 137:11365-, 2015

PubMed Abstract: Peptides can be developed as effective antagonists of protein-protein interactions, but conventional peptides (i.e., oligomers of l-α-amino acids) suffer from significant limitations in vivo. Short half-lives due to rapid proteolytic degradation and an inability to cross cell membranes often preclude biological applications of peptides. Oligomers that contain both α- and β-amino acid residues ("α/β-peptides") manifest decreased susceptibility to proteolytic degradation, and when properly designed these unnatural oligomers can mimic the protein-recognition properties of analogous "α-peptides". This report documents an extension of the α/β-peptide approach to target intracellular protein-protein interactions. Specifically, we have generated α/β-peptides based on a "stapled" Bim BH3 α-peptide, which contains a hydrocarbon cross-link to enhance α-helix stability. We show that a stapled α/β-peptide can structurally and functionally mimic the parent stapled α-peptide in its ability to enter certain types of cells and block protein-protein interactions associated with apoptotic signaling. However, the α/β-peptide is nearly 100-fold more resistant to proteolysis than is the parent stapled α-peptide. These results show that backbone modification, a strategy that has received relatively little attention in terms of peptide engineering for biomedical applications, can be combined with more commonly deployed peripheral modifications such as side chain cross-linking to produce synergistic benefits.

PubMed: 26317395
DOI: 10.1021/JACS.5B05896

Experimental method

X-RAY DIFFRACTION (2.24 Å)