5DC9: Crystal Structure Of Monobody As25/abl1 Sh2 Domain Complex, Crystal B

Citation:
Abstract
Bcr-Abl is a constitutively active kinase that causes chronic myelogenous leukemia. We have shown that a tandem fusion of two designed binding proteins, termed monobodies, directed to the interaction interface between the Src homology 2 (SH2) and kinase domains and to the phosphotyrosine-binding site of the SH2 domain, respectively, inhibits the Bcr-Abl kinase activity. Because the latter monobody inhibits processive phosphorylation by Bcr-Abl and the SH2-kinase interface is occluded in the active kinase, it remained undetermined whether targeting the SH2-kinase interface alone was sufficient for Bcr-Abl inhibition. To address this question, we generated new, higher affinity monobodies with single nanomolar KD values targeting the kinase-binding surface of SH2. Structural and mutagenesis studies revealed the molecular underpinnings of the monobody-SH2 interactions. Importantly, the new monobodies inhibited Bcr-Abl kinase activity in vitro and in cells, and they potently induced cell death in chronic myelogenous leukemia cell lines. This work provides strong evidence for the SH2-kinase interface as a pharmacologically tractable site for allosteric inhibition of Bcr-Abl.
PDB ID: 5DC9Download
MMDB ID: 136999
PDB Deposition Date: 2015/8/23
Updated in MMDB: 2016/05
Experimental Method:
x-ray diffraction
Resolution: 1.56  Å
Source Organism:
Similar Structures:
Biological Unit for 5DC9: dimeric; determined by author and by software (PISA)
Molecular Components in 5DC9
Label Count Molecule
Proteins (2 molecules)
1
Tyrosine-protein Kinase Abl1(Gene symbol: ABL1)
Molecule annotation
1
As25 Monobody
Molecule annotation
Chemicals (7 molecules)
1
5
2
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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