Amgen, Inc., Thousand Oaks, California 91320, United States.
Cytokinetics, Inc., South San Francisco, California 94080, United States.
Biochemistry. 2022 Apr 19;61(8):741-748. doi: 10.1021/acs.biochem.2c00084. Epub 2022 Mar 29.
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.
肌钙蛋白是一种位于肌节上的调节蛋白复合物，调节肌球蛋白与肌动蛋白丝的结合。与钙离子结合具有变构作用的肌钙蛋白的低分子量调节剂有可能改善心功能降低患者的心脏收缩力。在这里，我们通过结合使用溶液核磁共振和等温滴定量热法提出了一种合理设计肌钙蛋白调节剂的方法。与传统方法仅限于钙和激活剂结合的肌钙蛋白结构不同，在这里我们分析了在肌钙蛋白功能循环背景下激活剂的结构和热力学影响。这使我们提出了开发有效肌钙蛋白激活剂的原理。
