4esr | pdb_00004esr

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

spinqualitylabelsall models 4esr, resolution 1.53Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4esr is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: PEG Gene: AHI1 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [AHI1_HUMAN] Joubert syndrome;Joubert syndrome with ocular defect. The disease is caused by mutations affecting the gene represented in this entry. Function [AHI1_HUMAN] Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Publication Abstract from PubMed 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-A resolution reveals that it adopts canonical SH3 folding, with the exception of an unusual C-terminal alpha 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. 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.,Liu X, Chen M, Lobo P, An J, Grace Cheng SW, Moradian A, Morin GB, Van Petegem F, Jiang X Proteomics. 2012 May 24. doi: 10.1002/pmic.201100553. PMID:22623184 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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