Structural and Thermodynamic Model for the Activation of Cardiac Troponin

Abstract

Cardiac troponin is a regulatory protein complex located on the sarcomere that regulates the engagement of myosin on actin filaments. Low-molecular weight modulators of troponin that bind allosterically with the calcium ion have the potential to improve cardiac contractility in patients with reduced cardiac function. Here we propose an approach to the rational design of troponin modulators through the combined use of solution nuclear magnetic resonance and isothermal titration calorimetry methods. In contrast to traditional approaches limited to calcium and activator-bound troponin structures, here we analyzed the structural and thermodynamic impact of an activator in the context of the troponin functional cycle. This led us to propose a rationale for developing an efficacious troponin activator.

Cardiac Troponin Activator CK-963 Increases Cardiac Contractility in Rats

“…This outcome, along with the result of the sarcomere component swap experiment provides evidence that cardiac troponin is the target of CK-963 . The calorimetry result is consistent with previously reported ITC studies using an advanced member of this chemical series that were applied in combination with solution nuclear magnetic resonance to provide the basis for a structural and thermodynamic model for the activation of cardiac troponin …”

“…The calorimetry result is consistent with previously reported ITC studies using an advanced member of this chemical series that were applied in combination with solution nuclear magnetic resonance to provide the basis for a structural and thermodynamic model for the activation of cardiac troponin. 39 A series of experiments in anesthetized Sprague−Dawley rats were performed to evaluate the effect of the selective cardiac troponin activator CK-963 on cardiac function. CK-963 was tested on three separate occasions using continuous or stepwise infusion with cumulative doses as high as 199 mg/ kg.…”

“…The calorimetry result is consistent with previously reported ITC studies using an advanced member of this chemical series that were applied in combination with solution nuclear magnetic resonance to provide the basis for a structural and thermodynamic model for the activation of cardiac troponin. 39 …”

Биологические Маркеры Сепсиса

“…Сердечный тропонин представляет собой белковый комплекс, расположенный на саркомере, который регулирует взаимодействие миозина с актиновыми филаментами [89]. Уровень высокочувствительного сердечного тропонина Т (cTnT) -высокоэффективный прогностический маркер летальности у пациентов с сепсисом [90]; также он ассоциирован с 30-365-дневной смертностью у выживших после сепсиса [91].…”

Biological markers of sepsis

“…Cardiac troponin is a protein complex located on a sarcomere that regulates the interaction of myosin with actin filaments [93]. The high-sensitivity cardiac troponin T (cTnT) level is a highly effective prognostic marker for lethality in patients with sepsis [94].…”