Higher-order interactions of Bcr-Abl can broaden chronic myeloid leukemia (CML) drug repertoire

Yonglan Liu, Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Bcr-Abl, a nonreceptor tyrosine kinase, is associated with leukemias, especially chronic myeloid leukemia (CML). Deletion of Abl's N-terminal region, to which myristoyl is linked, renders the Bcr-Abl fusion oncoprotein constitutively active. The substitution of Abl's N-terminal region by Bcr enables Bcr-Abl oligomerization. Oligomerization is critical: it promotes clustering on the membrane, which is essential for potent MAPK signaling and cell proliferation. Here we decipher the Bcr-Abl specific, step-by-step oligomerization process, identify a specific packing surface, determine exactly how the process is structured and identify its key elements. Bcr's coiled coil (CC) domain at the N-terminal controls Bcr-Abl oligomerization. Crystallography validated oligomerization via Bcr-Abl dimerization between two Bcr CC domains, with tetramerization via tight packing between two binary assemblies. However, the structural principles guiding Bcr CC domain oligomerization are unknown, hindering mechanistic understanding and drugs exploiting it. Using molecular dynamics (MD) simulations, we determine that the binary complex of the Bcr CC domain serves as a basic unit in the quaternary complex providing a specific surface for dimer–dimer packing and higher-order oligomerization. We discover that the small α1-helix is the key. In the binary assembly, the helix forms interchain aromatic dimeric packing, and in the quaternary assembly, it contributes to the specific dimer–dimer packing. Our mechanism is supported by the experimental literature. It offers the key elements controlling this process which can expand the drug discovery strategy, including by Bcr CC-derived peptides, and candidate residues for small covalent drugs, toward quenching oligomerization, supplementing competitive and allosteric tyrosine kinase inhibitors.

Original languageEnglish
Article numbere4504
JournalProtein Science
Volume32
Issue number1
DOIs
StatePublished - Jan 2023

Funding

FundersFunder number
U.S. Government
National Institutes of Health
U.S. Department of Health and Human Services
National Cancer Institute
National Health Insurance AdministrationHHSN261201500003I

    Keywords

    • Bcr
    • covalent inhibitors
    • fusion protein
    • molecular dynamics
    • oligomerization domain
    • peptide inhibitor

    Fingerprint

    Dive into the research topics of 'Higher-order interactions of Bcr-Abl can broaden chronic myeloid leukemia (CML) drug repertoire'. Together they form a unique fingerprint.

    Cite this