7uh9
NMR structure of the cNTnC-cTnI chimera bound to W8NMR structure of the cNTnC-cTnI chimera bound to W8
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 PubMedW7 is a sarcomere inhibitor that decreases the calcium sensitivity of force development in cardiac muscle. W7 binds to the interface of the regulatory domain of cardiac troponin C (cNTnC) and the switch region of troponin I (cTnI), decreasing the binding of cTnI to cNTnC, presumably by electrostatic repulsion between the -NH3(+) group of W7 and basic amino acids in cTnI. W7 analogs with a -CO2(-) tail are inactive. To evaluate the importance of the location of the charged -NH3(+), we used a series of compounds W4, W6, W8, and W9, which have three less, one less, one more, and two more methylene groups in the tail region than W7. W6, W8, and W9 all bind tighter to cNTnC-cTnI chimera (cChimera) than W7, while W4 binds weaker. W4 and, strikingly, W6 have no effect on calcium sensitivity of force generation, while W8 and W9 decrease calcium sensitivity, but less than W7. The structures of the cChimera-W6 and cChimera-W8 complexes reveal that W6 and W8 bind to the same hydrophobic cleft as W7, with the aliphatic tail taking a similar route to the surface. NMR relaxation data show that internal flexibility in the tail of W7 is very limited. Alignment of the cChimera-W7 structure with the recent cryoEM structures of the cardiac sarcomere in the diastolic and systolic states reveals the critical location of the amino group. Small molecule induced structural changes can therefore affect the tightly balanced equilibrium between tethered components required for rapid contraction. Drugging the Sarcomere, a Delicate Balance: Position of N-Terminal Charge of the Inhibitor W7.,Cai F, Kampourakis T, Cockburn KT, Sykes BD ACS Chem Biol. 2022 Jun 1. doi: 10.1021/acschembio.2c00126. PMID:35649123[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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