6mv3 | pdb_00006mv3
NMR structure of the cNTnC-cTnI chimera bound to calcium desensitizer W7
Structural highlights
Disease[TNNC1_HUMAN] Defects in TNNC1 are the cause of cardiomyopathy dilated type 1Z (CMD1Z) [MIM:611879]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.[1] Defects in TNNC1 are the cause of familial hypertrophic cardiomyopathy type 13 (CMH13) [MIM:613243]. A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.[2] [3] [4] [5] Function[TNNC1_HUMAN] Troponin is the central regulatory protein of striated muscle contraction. Tn consists of three components: Tn-I which is the inhibitor of actomyosin ATPase, Tn-T which contains the binding site for tropomyosin and Tn-C. The binding of calcium to Tn-C abolishes the inhibitory action of Tn on actin filaments. Publication Abstract from PubMedCompounds that directly modulate the affinity of the thin filament calcium regulatory proteins in cardiac muscle have potential for treating heart disease. A recent "proof of concept" study showed that the desensitizer W7 can correct hyper-calcium-sensitive sarcomeres from RCM R193H inhibitory subunit troponin I (cTnI) transgenic mice. We have determined the high-resolution nuclear magnetic resonance solution structure of W7 bound to the regulatory domain of calcium binding subunit troponin C (cNTnC)-cTnI cChimera designed to represent the key aspects of the cTnC-cTnI interface. The structure shows that W7 does not perturb the overall structure of the cTnC-cTnI interface, with the helical structure and position of the cTnI switch region remaining intact upon W7 binding. The naphthalene ring of W7 sits in the hydrophobic pocket created by the cNTnC-cTnI switch peptide interface, while the positively charged amine tail extends into the solvent. The positively charged tail of W7 is in the proximity of Arg147 of the cTnI switch region, supporting the suggestion that electrostatic repulsion is an aspect underlying the mechanism of desensitization. Ser84 (replacing the unique Cys84 in cTnC reported to make a reversible covalent bond with levosimendan) also contacts W7. Structural Changes Induced by the Binding of the Calcium Desensitizer W7 to Cardiac Troponin.,Cai F, Hwang PM, Sykes BD Biochemistry. 2018 Nov 6. doi: 10.1021/acs.biochem.8b00882. PMID:30376637[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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