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

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 CCderived peptides, and candidate residues for small covalent drugs, toward quenching oligomerization, supplementing competitive and allosteric tyrosine kinase inhibitors.

K128 ubiquitination constrains RAS activity by expanding its binding interface with GAP proteins

“…We performed MD simulations using the updated CHARMM all-atom force field (version 36 m) to construct the set of starting points and relax the systems to a production-ready stage. Our simulations followed closely the same protocol as in our previous work (Grudzien et al, 2022 ; Jang et al, 2021 ; Liu et al, 2023 ). The TIP3 water model was used to solve the system.…”

SHP2–EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action

“…We performed all-atom MD simulations for all simulation systems in the NAMD 2.13 package with the CHARMM all-atom additive force field (version C36m). , The simulation protocols closely follow those employed in our previous works. ,,− In the pre-equilibrium stage, several cycles of minimization and short dynamics were executed before initiating the production runs to remove bad atom contacts. The production runs for each system were conducted under the NPT ensemble with 3D periodic boundary conditions.…”