An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models
Ping Wang, … , Sakthivel Sadayappan, Hesham A. Sadek
Ping Wang, … , Sakthivel Sadayappan, Hesham A. Sadek
Published February 17, 2025
Citation Information: J Clin Invest. 2025;135(4):e174081. https://doi.org/10.1172/JCI174081.
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Research Article Cardiology

An FDA-approved drug structurally and phenotypically corrects the K210del mutation in genetic cardiomyopathy models

Abstract

Dilated cardiomyopathy (DCM) due to genetic disorders results in decreased myocardial contractility, leading to high morbidity and mortality rates. There are several therapeutic challenges in treating DCM, including poor understanding of the underlying mechanism of impaired myocardial contractility and the difficulty of developing targeted therapies to reverse mutation-specific pathologies. In this report, we focused on K210del, a DCM-causing mutation, due to 3-nucleotide deletion of sarcomeric troponin T (TnnT), resulting in loss of Lysine210. We resolved the crystal structure of the troponin complex carrying the K210del mutation. K210del induced an allosteric shift in the troponin complex resulting in distortion of activation Ca2+-binding domain of troponin C (TnnC) at S69, resulting in calcium discoordination. Next, we adopted a structure-based drug repurposing approach to identify bisphosphonate risedronate as a potential structural corrector for the mutant troponin complex. Cocrystallization of risedronate with the mutant troponin complex restored the normal configuration of S69 and calcium coordination. Risedronate normalized force generation in K210del patient-induced pluripotent stem cell–derived (iPSC-derived) cardiomyocytes and improved calcium sensitivity in skinned papillary muscles isolated from K210del mice. Systemic administration of risedronate to K210del mice normalized left ventricular ejection fraction. Collectively, these results identify the structural basis for decreased calcium sensitivity in K210del and highlight structural and phenotypic correction as a potential therapeutic strategy in genetic cardiomyopathies.

Authors

Ping Wang, Mahmoud Salama Ahmed, Ngoc Uyen Nhi Nguyen, Ivan Menendez-Montes, Ching-Cheng Hsu, Ayman B. Farag, Suwannee Thet, Nicholas T. Lam, Janaka P. Wansapura, Eric Crossley, Ning Ma, Shane Rui Zhao, Tiejun Zhang, Sachio Morimoto, Rohit Singh, Waleed Elhelaly, Tara C. Tassin, Alisson C. Cardoso, Noelle S. Williams, Hayley L. Pointer, David A. Elliott, James W. McNamara, Kevin I. Watt, Enzo R. Porrello, Sakthivel Sadayappan, Hesham A. Sadek

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Figure 1

Structure characterization of WT and ΔK210 complex.

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Structure characterization of WT and ΔK210 complex. (A) Fluorescence-bas...
(A) Fluorescence-based measurement of the binding affinity of Ca2+ for WT and K210del to troponin complex. (B) Representation of the overall structure of ΔK210 and WT complex. TnnC is shown in green, TnnT is shown in orange, and TnnI is shown in purple. Ca2+ is shown in pink sphere. This color scheme is consistent for the ΔK210 complex in all the following figures unless otherwise specified. (C) Representation showing superimposition of WT (gray) and ΔK210. (D) Surface representation colored by the vacuum electrostatic potential of WT in the same orientation as in C. (E) Surface representation colored by the vacuum electrostatic potential of the ΔK210 complex in the same orientation as in C. (F) Highlight of K210 deletion site (in green dash circle) and hinge region of TnnT and TnnI showing superimposition of WT (gray) and ΔK210 (TnnC in green, TnnT in orange, and TnnI in purple). Specific residues in the hinge region are shown in stick representation. (G) Representation showing superimposition of Ca2+-binding domains in WT (gray) and ΔK210 (TnnC in green, TnnT in orange and TnnI in purple). (H) Detailed interaction of Ca2+ in the activation Ca2+-binding pocket for TnnC in ΔK210 complex. Specific residues coordinating the Ca2+are shown in green stick representation. Hydrogen bonds are indicated with black dashed lines. (I) Detailed interaction of Ca2+ in the activation Ca2+-binding pocket for TnnC in WT complex. Specific residues coordinating the Ca2+are shown in gray stick representation. Hydrogen bonds are indicated with black dashed lines. (J) Representation showing superimposition of the detailed interaction of Ca2+ in the activation Ca2+-binding pocket for TnnC in WT complex (gray) and ΔK210 complex (green). Data are presented as mean ± SEM; unpaired 2-sided t test. ****P < 0.0001.