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A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
Published on: November 2, 2018
Crystal structure of the T315I mutant of AbI kinase
Tianjun Zhou1, Lois Parillon, Feng Li
1ARIAD Pharmaceuticals Inc, 26 Landsdowne St., Cambridge, MA 02139, USA.
Abstract:
Imatinib (Gleevec) is currently the frontline therapy for chronic myeloid leukemia (CML), a disease characterized by the presence of a constitutively activated chimeric tyrosine kinase protein Bcr-AbI. However, drug resistance often occurs at later stages of the disease, principally because of the occurrence of mutations in the kinase domain. Second generation Bcr-AbI inhibitors, such as dasatinib and nilotinib are capable of inhibiting many imatinib-resistant forms of the kinase but not the form in which threonine is mutated to isoleucine at the gatekeeper position (T315I). In this study, we present the crystal structure of the kinase domain of the c-AbI T315I mutant, as well as the wild-type form, in complex with a pyrrolopyridine inhibitor, PPY-A. The side chain of Ile315 is accommodated in the AbI T315I mutant structure without large conformational changes proximal to the site of mutation. In contrast to other inhibitors, such as imatinib and dasatinib, PPY-A does not occupy the hydrophobic pocket behind the gatekeeper residue. This binding mode, coupled with augmented contacts with the glycine-rich loop, appears to be critical for its ability to override the T315I mutation. The data presented here may provide structural guidance for the design of clinically useful inhibitors of Bcr-AbI T315I.
Insights
A novel pyrrolopyridine inhibitor, PPY-A, effectively targets the T315I mutation in chronic myeloid leukemia (CML). This inhibitor overcomes resistance by utilizing a unique binding mode, offering new hope for CML treatment.
Area of Science:
- Biochemistry
- Structural Biology
- Oncology
Background:
- Chronic myeloid leukemia (CML) is treated with imatinib, targeting the Bcr-Abl tyrosine kinase.
- Drug resistance, often due to mutations like T315I, limits imatinib efficacy.
- Second-generation inhibitors are ineffective against the T315I gatekeeper mutation.
Purpose of the Study:
- To determine the crystal structure of the c-Abl T315I mutant kinase domain.
- To elucidate the binding mechanism of a novel pyrrolopyridine inhibitor (PPY-A) against the T315I mutant.
- To provide structural insights for developing new CML therapies.
Main Methods:
- X-ray crystallography of wild-type and T315I mutant c-Abl kinase domains.
- Complex formation with the pyrrolopyridine inhibitor PPY-A.
- Structural analysis of inhibitor binding interactions.
Main Results:
- The crystal structure of c-Abl T315I mutant with PPY-A was determined.
- The T315I mutation accommodates the isoleucine side chain without major structural changes.
- PPY-A exhibits a distinct binding mode, avoiding the hydrophobic pocket and engaging the glycine-rich loop, which is key to overcoming T315I resistance.
Conclusions:
- PPY-A effectively inhibits the T315I Bcr-Abl mutant.
- The unique binding mode of PPY-A is critical for overcoming gatekeeper mutations.
- Structural data can guide the design of next-generation CML inhibitors targeting resistant mutations.
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