A Src-like inactive conformation in the abl tyrosine kinase domain

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Improper Abl tyrosine kinase activation drives chronic myeloid leukemia (CML).
• Imatinib's specificity relies on targeting an inactive Abl conformation with a flipped Asp-Phe-Gly (DFG) motif.
• Related Src kinases lack this DFG motif flip in inactive states, and imatinib does not inhibit c-Src.

Purpose of the Study:

• To present a novel inactive conformation of the Abl kinase domain.
• To investigate the structural basis for Abl kinase's distinct inactive states.
• To explore the implications of these conformations for imatinib resistance.

Main Methods:

• X-ray crystallography of the Abl kinase domain with an ATP-peptide conjugate.
• Molecular dynamics simulations.
• Analysis of resistance mutations in BCR-Abl.

Main Results:

• A crystal structure of Abl kinase in an inactive conformation resembling Src kinases was determined.
• Features facilitating the DFG motif flip in the Src-like inactive Abl structure were identified.
• Certain imatinib-resistance mutations destabilize this Src-like inactive conformation.

Conclusions:

• The Abl kinase domain can interconvert between different inactive conformations.
• This conformational flexibility is a key characteristic of the Abl kinase domain.
• Understanding these states may inform future CML therapeutic strategies.