1lky

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spinqualitylabelsall models 1lky, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Structure of the wild-type TEL-SAM polymer

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

BACKGROUND: TEL is a transcriptional repressor containing a SAM domain, that forms a helical polymer. In a number of hematologic malignancies, chromosomal translocations lead to aberrant fusions of TEL-SAM to a, variety of other proteins, including many tyrosine kinases. TEL-SAM, polymerization results in constitutive activation of the tyrosine kinase, domains to which it becomes fused, leading to cell transformation. Thus, inhibitors of TEL-SAM self-association could abrogate transformation in, these cells. In previous work, we determined the structure of a mutant, TEL-SAM polymer bearing a Val to Glu substitution in center of the subunit, interface. It remained unclear how much the mutation affected the, architecture of the polymer, however. RESULTS: Here we determine the, structure of the native polymer interface. To accomplish this goal, we, introduced mutations that block polymer extension, producing a heterodimer, with a wild-type interface. We find that the structure of the wild-type, polymer interface is quite similar to the mutant structure determined, previously. With the structure of the native interface, it is possible to, evaluate the potential for developing therapeutic inhibitors of the, interaction. We find that the interacting surfaces of the protein are, relatively flat, containing no obvious pockets for the design of small, molecule inhibitors. CONCLUSION: Our results confirm the architecture of, the TEL-SAM polymer proposed previously based on a mutant structure. The, fact that the interface contains no obvious potential binding pockets, suggests that it may be difficult to find small molecule inhibitors to, treat malignancies in this way.

Disease

Known diseases associated with this structure: Leukemia, acute myeloid, somatic OMIM:[600618]

About this Structure

1LKY is a Protein complex structure of sequences from Homo sapiens with as ligand. Full crystallographic information is available from OCA.

Reference

Native interface of the SAM domain polymer of TEL., Tran HH, Kim CA, Faham S, Siddall MC, Bowie JU, BMC Struct Biol. 2002 Aug 22;2:5. PMID:12193272

Page seeded by OCA on Fri Feb 15 16:19:08 2008