4k5a

Co-crystallization with conformation-specific designed ankyrin repeat proteins explains the conformational flexibility of BCL-W

spinqualitylabelsall models 4k5a, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4k5a is a 2 chain structure with sequence from "bacillus_coli"_migula_1895 "bacillus coli" migula 1895 and Bovin. Full crystallographic information is available from OCA. Related: 4k5b Gene: BCL2L2 (BOVIN) Activity: Glucokinase, with EC number 2.7.1.2 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed 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 a resolution of 1.5 and 1.85A, in which the structure of BCL-W is virtually identical, and in both structures BCL-W adopts a conformation extremely similar to the ligand-free conformation of its closest relative BCL-XL. 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. Co-crystallization with conformation-specific designed ankyrin repeat proteins explains the conformational flexibility of BCL-W.,Schilling J, Schoppe J, Sauer E, Pluckthun A J Mol Biol. 2014 Apr 17. pii: S0022-2836(14)00194-6. doi:, 10.1016/j.jmb.2014.04.010. PMID:24747052 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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