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Structural Changes Induced by the Binding of the Calcium Desensitizer W7 to Cardiac Troponin

Fangze Cai1, Peter M Hwang2, Brian D Sykes1

  • 1Department of Biochemistry , University of Alberta , Edmonton , Alberta , Canada T6G 2H7.

Biochemistry
|October 31, 2018
PubMed

Insights

The drug W7 corrects heart muscle issues by binding to cardiac troponin C and troponin I. This structural study reveals how W7 interacts with these proteins, offering insights into treating heart disease.

Area of Science:

  • Biochemistry
  • Cardiovascular Biology
  • Structural Biology

Background:

  • Compounds modulating cardiac muscle thin filament proteins offer potential for heart disease treatment.
  • The desensitizer W7 has shown promise in correcting hyper-calcium-sensitive sarcomeres.
  • Understanding the molecular interactions of W7 is crucial for therapeutic development.

Purpose of the Study:

  • To determine the high-resolution structure of W7 bound to the cardiac troponin C (cNTnC)-cardiac troponin I (cTnI) interface.
  • To elucidate the molecular mechanism by which W7 desensitizes cardiac muscle calcium sensitivity.

Main Methods:

  • High-resolution nuclear magnetic resonance (NMR) solution structure determination.
  • Utilized a cNTnC-cTnI chimera to model the key aspects of the native interface.

Main Results:

  • The W7-bound structure reveals W7 does not disrupt the overall cTnC-cTnI interface structure.
  • W7's naphthalene ring occupies a hydrophobic pocket at the interface, while its tail extends towards the solvent.
  • W7's tail is near Arg147 of cTnI, supporting an electrostatic repulsion mechanism for desensitization.
  • Ser84 of cTnC also interacts with W7.

Conclusions:

  • W7 binding preserves the structural integrity of the cTnC-cTnI interface.
  • The interaction suggests an electrostatic mechanism for W7-mediated desensitization in cardiac muscle.
  • This structural insight aids in the development of novel therapeutics for heart conditions.

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