PDBsum entry 4k5a

Apoptosis

PDB id: 4k5a

Contents

Protein chains

164 a.a.

161 a.a.

Waters ×402

PDB id:

4k5a

Name:

Apoptosis

Title:

Co-crystallization with conformation-specific designed ankyrin repeat proteins explains the conformational flexibility of bcl-w

Structure:

Bcl-2-like protein 2. Chain: a. Fragment: unp residues 2-171. Synonym: bcl2-l-2, apoptosis regulator bcl-w. Engineered: yes. Mutation: yes. Designed ankyrin repeat protein 013_d12. Chain: b. Engineered: yes

Source:

Bos taurus. Bovine,cow,domestic cattle,domestic cow. Organism_taxid: 9913. Gene: bcl2l2. Expressed in: escherichia coli. Expression_system_taxid: 562. Escherichia coli. Organism_taxid: 562.

Resolution:

1.50Å R-factor: 0.158 R-free: 0.190

Authors:

J.Schilling,J.Schoeppe,E.Sauer,A.Plueckthun

Key ref:

J.Schilling et al. (2014). Co-crystallization with conformation-specific designed ankyrin repeat proteins explains the conformational flexibility of BCL-W. J Mol Biol, 426, 2346-2362. PubMed id: 24747052 DOI: 10.1016/j.jmb.2014.04.010

Date:

14-Apr-13 Release date: 16-Apr-14

Protein chain

Q1RMX3  (B2CL2_BOVIN) -  Bcl-2-like protein 2 from Bos taurus

Seq: 193 a.a.

Struc: 164 a.a.*

Protein chain

No UniProt id for this chain

Struc: 161 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chain A: E.C.?

DOI no: 10.1016/j.jmb.2014.04.010

J Mol Biol 426:2346-2362 (2014)

PubMed id: 24747052

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

J.Schilling, J.Schöppe, E.Sauer, A.Plückthun.

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.