4ESR

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

Summary for 4ESR

• Entry DOI: 10.2210/pdb4esr/pdb
• Descriptor: Jouberin, DI(HYDROXYETHYL)ETHER (3 entities in total)
• Functional Keywords: ahi-1, ahi1, ahi-1 sh3 domain, sh3 domain, dynamin-2, protein binding, chronic myeloid leukemia
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytoskeleton, cilium basal body : Q8N157
• Total number of polymer chains: 2
• Total formula weight: 16227.67

Authors

Van Petegem, X.F.,Liu, P.X.,Lobo, P.,Jiang, X. (deposition date: 2012-04-23, release date: 2012-06-06, Last modification date: 2024-02-28)

Primary citation

Liu, X.,Chen, M.,Lobo, P.,An, J.,Grace Cheng, S.W.,Moradian, A.,Morin, G.B.,Van Petegem, F.,Jiang, X.
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.
Proteomics, 12:2094-2106, 2012

PubMed Abstract: 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.

PubMed: 22623184
DOI: 10.1002/pmic.201100553

Experimental method

X-RAY DIFFRACTION (1.53 Å)