4K5B
Co-crystallization with conformation-specific designed ankyrin repeat proteins explains the conformational flexibility of BCL-W
Summary for 4K5B
| Entry DOI | 10.2210/pdb4k5b/pdb |
| Related | 4K5A |
| Descriptor | Apoptosis regulator BCL-W, Bcl-2-like protein 2 (3 entities in total) |
| Functional Keywords | apoptosis, anti-apoptotic bcl-2 family, bcl-w;crystal structure, ligand binding-competent conformation, darpins |
| Biological source | Escherichia coli More |
| Cellular location | Mitochondrion membrane; Peripheral membrane protein (By similarity): 4K5B |
| Total number of polymer chains | 4 |
| Total formula weight | 76808.17 |
| Authors | Schilling, J.,Schoeppe, J.,Sauer, E.,Plueckthun, A. (deposition date: 2013-04-14, release date: 2014-04-16, Last modification date: 2024-03-20) |
| Primary citation | Schilling, J.,Schoppe, J.,Sauer, E.,Pluckthun, A. Co-Crystallization with Conformation-Specific Designed Ankyrin Repeat Proteins Explains the Conformational Flexibility of BCL-W J.Mol.Biol., 426:2346-2362, 2014 Cited by PubMed Abstract: BCL-W is a member of the BCL-2 family of anti-apoptotic proteins. A key event in the regulation of apoptosis is the heterodimerization between anti-apoptotic and pro-apoptotic family members, which involves a conserved surface-exposed groove on the anti-apoptotic proteins. Crystal structures of the ligand binding-competent conformation exist for all anti-apoptotic family members, with the exception of BCL-W, due to the flexibility of the BCL-W groove region. Existing structures had suggested major deviations of the BCL-W groove region from the otherwise structurally highly related remaining anti-apoptotic family members. To capture its ligand binding-competent conformation by counteracting the conformational flexibility of the BCL-W groove, we had selected high-affinity groove-binding designed ankyrin repeat proteins (DARPins) using ribosome display. We now determined two high-resolution crystal structures of human BCL-W in complex with different DARPins at resolutions 1.5 and 1.85Å, in which the structure of BCL-W is virtually identical, and BCL-W adopts a conformation extremely similar to the ligand-free conformation of its closest relative BCL-XL in both structures. However, distinct differences to all previous BCL-W structures are evident, notably in the ligand-binding region. We provide the first structural explanation for the conformational flexibility of the BCL-W groove region in comparison to other BCL-2 family members. Due to the importance of the anti-apoptotic BCL-2 family as drug targets, the presented crystal structure of ligand binding-competent BCL-W may serve as a valuable basis for structure-based drug design in the future and provides a missing piece for the structural characterization of this protein family. PubMed: 24747052DOI: 10.1016/j.jmb.2014.04.010 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
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