PDBsum entry 4esr

Protein binding

PDB id: 4esr

Contents

Protein chain

65 a.a.

Ligands

PEG ×3

Waters ×166

PDB id:

4esr

Name:

Protein binding

Title:

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

Structure:

Jouberin. Chain: a, b. Fragment: ahi-1 sh3 domain (unp residues 1048-1116). Synonym: abelson helper integration site 1 protein homolog, ahi-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ahi1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.53Å R-factor: 0.125 R-free: 0.139

Authors:

X.F.Van Petegem,P.X.Liu,P.Lobo,X.Jiang

Key ref:

X.Liu et al. (2012). 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. PubMed id: 22623184

Date:

23-Apr-12 Release date: 06-Jun-12

Protein chains

Q8N157  (AHI1_HUMAN) -  Jouberin from Homo sapiens

Seq: 1196 a.a.

Struc: 65 a.a.

Proteomics 12:2094-2106 (2012)

PubMed id: 22623184

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.

X.Liu, M.Chen, P.Lobo, J.An, S.W.Grace Cheng, A.Moradian, G.B.Morin, F.Van Petegem, X.Jiang.

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.