4MI8
Crystal structure of the complex of murine gamma-herpesvirus 68 Bcl-2 homolog M11 and a Beclin 1 BH3 domain-derived peptide
Summary for 4MI8
| Entry DOI | 10.2210/pdb4mi8/pdb |
| Related | 3DVU |
| Descriptor | Bcl-2 homolog (Gene 16?), Beclin-1, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | bh3d, bcl-2 family, anti-apoptotic and anti-autophagic activities, viral protein-apoptosis complex, viral protein/apoptosis |
| Biological source | Murid herpesvirus 4 (MuHV-4) More |
| Cellular location | Cytoplasm . Beclin-1-C 35 kDa: Mitochondrion . Beclin-1-C 37 kDa: Mitochondrion : Q14457 |
| Total number of polymer chains | 4 |
| Total formula weight | 39380.49 |
| Authors | |
| Primary citation | Su, M.,Mei, Y.,Sanishvili, R.,Levine, B.,Colbert, C.L.,Sinha, S. Targeting gamma-herpesvirus 68 Bcl-2-mediated down-regulation of autophagy. J.Biol.Chem., 289:8029-8040, 2014 Cited by PubMed Abstract: γ-herpesviruses (γHVs) are common human pathogens that encode homologs of the anti-apoptotic cellular Bcl-2 proteins, which are critical to viral reactivation and oncogenic transformation. The murine γHV68 provides a tractable in vivo model for understanding general features of these important human pathogens. Bcl-XL, a cellular Bcl-2 homolog, and the murine γHV68 Bcl-2 homolog, M11, both bind to a BH3 domain within the key autophagy effector Beclin 1 with comparable affinities, resulting in the down-regulation of Beclin 1-mediated autophagy. Despite this similarity, differences in residues lining the binding site of M11 and Bcl-XL dictate varying affinities for the different BH3 domain-containing proteins. Here we delineate Beclin 1 differential specificity determinants for binding to M11 or Bcl-XL by quantifying autophagy levels in cells expressing different Beclin 1 mutants and either M11 or Bcl-XL, and we show that a G120E/D121A Beclin 1 mutant selectively prevents down-regulation of Beclin 1-mediated autophagy by Bcl-XL, but not by M11. We use isothermal titration calorimetry to identify a Beclin 1 BH3 domain-derived peptide that selectively binds to M11, but not to Bcl-XL. The x-ray crystal structure of this peptide bound to M11 reveals the mechanism by which the M11 BH3 domain-binding groove accommodates this M11-specific peptide. This information was used to develop a cell-permeable peptide inhibitor that selectively inhibits M11-mediated, but not Bcl-XL-mediated, down-regulation of autophagy. PubMed: 24443581DOI: 10.1074/jbc.M113.515361 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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