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Small molecule-mediated refolding and activation of myosin motor function
Michael B Radke1, Manuel H Taft, Britta Stapel
1Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany.
Elife
|February 13, 2014
Summary
The small molecule EMD 57033 binds to myosin, enhancing its activity and protecting it from heat damage. This molecule shows potential for treating heart failure and protein misfolding diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- The small molecule EMD 57033 is known to stimulate actomyosin ATPase activity and myofilament contractility.
- The precise mechanism of action for EMD 57033 at the molecular level remained to be fully elucidated.
Purpose of the Study:
- To investigate the binding site and molecular mechanism of EMD 57033.
- To determine the effects of EMD 57033 on myosin function and stability under thermal stress.
- To explore the therapeutic potential of EMD 57033 in cardiac and protein misfolding diseases.
Main Methods:
- Biochemical assays to measure ATPase activity and protein-ligand interactions.
- Thermal stress experiments to assess protein stability and denaturation.
- Studies on isolated cardiomyocytes to evaluate cellular responses.
Main Results:
- EMD 57033 binds to an allosteric pocket in the myosin motor domain.
- EMD 57033 binding protects myosin from heat stress and denaturation, increasing ATPase activity and actin affinity over 10-fold.
- Addition of EMD 57033 refolded and reactivated heat-inactivated cardiac myosin.
- EMD 57033 suppressed atrial natriuretic peptide expression in heat-stressed cardiomyocytes.
Conclusions:
- EMD 57033 acts as an allosteric effector of myosin, enhancing its enzymatic function and stability.
- EMD 57033 exhibits a broader range of activities than previously recognized for small molecules.
- Allosteric effectors like EMD 57033 hold promise for treating heart failure, myopathies, and protein misfolding diseases.
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