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A Maltose-Binding Protein Fusion Construct Yields a Robust Crystallography Platform for MCL1
Matthew C Clifton1, David M Dranow1, Alison Leed2
1Beryllium, Bedford, Massachusetts, United States of America.
Plos One
|April 25, 2015
Summary
A novel maltose-binding protein (MBP) fusion platform enabled the first crystal structures of MCL1, including ligand-bound forms. This breakthrough advances structure-based drug design for MCL1 inhibitors.
Area of Science:
- Structural Biology
- Drug Discovery
- Biochemistry
Background:
- MCL1 is a validated target for cancer therapy, but its structural characterization by crystallography has been challenging.
- Previous efforts to obtain high-resolution structures of MCL1 for drug design have been limited.
Purpose of the Study:
- To develop a robust crystallography platform for MCL1 structure determination.
- To obtain apo and ligand-bound structures of MCL1 to facilitate structure-based drug design.
Main Methods:
- A fusion protein construct involving maltose-binding protein (MBP) and MCL1 was engineered.
- Crystallization of the MBP-MCL1 fusion protein was performed.
- X-ray crystallography was used to determine apo and ligand-bound structures.
Main Results:
- The MBP-MCL1 fusion enabled the generation of the first apo MCL1 crystal structure.
- Five distinct ligand-bound structures of MCL1 were obtained.
- Novel inhibitor binding modes were identified in the ligand-independent crystal form.
Conclusions:
- The MBP-MCL1 fusion protein serves as a robust platform for MCL1 crystallography.
- These structures significantly enhance the understanding of MCL1 ligand interactions.
- This work is expected to accelerate the structure-based optimization of high-affinity MCL1 inhibitors for therapeutic development.
