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PDBsum entry 4k5a
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References listed in PDB file
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Key reference
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Title
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Co-Crystallization with conformation-Specific designed ankyrin repeat proteins explains the conformational flexibility of bcl-W.
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Authors
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J.Schilling,
J.Schöppe,
E.Sauer,
A.Plückthun.
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Ref.
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J Mol Biol, 2014,
426,
2346-2362.
[DOI no: ]
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PubMed id
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Abstract
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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.
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