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The calcium sensitizer drug MCI-154 binds the structural C-terminal domain of cardiac troponin C.


ABSTRACT: The compound MCI-154 was previously shown to increase the calcium sensitivity of cardiac muscle contraction. Using solution NMR spectroscopy, we demonstrate that MCI-154 interacts with the calcium-sensing subunit of the cardiac troponin complex, cardiac troponin C (cTnC). Surprisingly, however, it binds only to the structural C-terminal domain of cTnC (cCTnC), and not to the regulatory N-terminal domain (cNTnC) that determines the calcium sensitivity of cardiac muscle. Physiologically, cTnC is always bound to cardiac troponin I (cTnI), so we examined its interaction with MCI-154 in the presence of two soluble constructs, cTnI1-77 and cTnI135-209, which contain all of the segments of cTnI known to interact with cTnC. Neither the cTnC-cTnI1-77 complex nor the cTnC-cTnI135-209 complex binds to MCI-154. Since residues 39-60 of cTnI are known to bind tightly to the cCTnC domain to form a structured core that is invariant throughout the cardiac cycle, we conclude that MCI-154 does not bind to cTnC when it is part of the intact cardiac troponin complex. Thus, MCI-154 likely exerts its calcium sensitizing effect by interacting with a target other than cardiac troponin.

SUBMITTER: Li MX 

PROVIDER: S-EPMC6218639 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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The calcium sensitizer drug MCI-154 binds the structural C-terminal domain of cardiac troponin C.

Li Monica X MX   Gelozia Shorena S   Danmaliki Gaddafi I GI   Wen Yurong Y   Liu Philip B PB   Lemieux M Joanne MJ   West Frederick G FG   Sykes Brian D BD   Hwang Peter M PM  

Biochemistry and biophysics reports 20181101


The compound MCI-154 was previously shown to increase the calcium sensitivity of cardiac muscle contraction. Using solution NMR spectroscopy, we demonstrate that MCI-154 interacts with the calcium-sensing subunit of the cardiac troponin complex, cardiac troponin C (cTnC). Surprisingly, however, it binds only to the structural C-terminal domain of cTnC (cCTnC), and not to the regulatory N-terminal domain (cNTnC) that determines the calcium sensitivity of cardiac muscle. Physiologically, cTnC is a  ...[more]

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