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PDBsum entry 4esr
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Protein binding
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PDB id
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4esr
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References listed in PDB file
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Key reference
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Title
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Molecular and structural characterization of the sh3 domain of ahi-1 in regulation of cellular resistance of bcr-Abl(+) chronic myeloid leukemia cells to tyrosine kinase inhibitors.
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Authors
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X.Liu,
M.Chen,
P.Lobo,
J.An,
S.W.Grace cheng,
A.Moradian,
G.B.Morin,
F.Van petegem,
X.Jiang.
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Ref.
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Proteomics, 2012,
12,
2094-2106.
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PubMed id
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Abstract
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ABL tyrosine kinase inhibitor (TKI) therapy induces clinical remission in
chronic myeloid leukemia (CML) patients but early relapses and later emergence
of TKI-resistant disease remain problematic. We recently demonstrated that the
AHI-1 oncogene physically interacts with BCR-ABL and JAK2 and mediates cellular
resistance to TKI in CML stem/progenitor cells. We now show that deletion of the
SH3 domain of AHI-1 significantly enhances apoptotic response of BCR-ABL(+)
cells to TKIs compared to cells expressing full-length AHI-1. We have also
discovered a novel interaction between AHI-1 and Dynamin-2, a GTPase, through
the AHI-1 SH3 domain. The crystal structure of the AHI-1 SH3 domain at 1.53-Å
resolution reveals that it adopts canonical SH3 folding, with the exception of
an unusual C-terminal α helix. PD1R peptide, known to interact with the PI3K
SH3 domain, was used to model the binding pattern between the AHI-1 SH3 domain
and its ligands. These studies showed that an "Arg-Arg-Trp" stack may
form within the binding interface, providing a potential target site for
designing specific drugs. The crystal structure of the AHI-1 SH3 domain thus
provides a valuable tool for identification of key interaction sites in
regulation of drug resistance and for the development of small molecule
inhibitors for CML.
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