期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 48, 期 5, 页码 925-933出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2010.01.016
关键词
Troponin; Structure; Drugs; Mechanism; Inhibition
资金
- Canadian Institutes of Health Research [MOP 37760]
- Natural Science and Engineering Research Council of Canada
- University of Alberta
- National Institutes of Health [R01 HL-085234]
- Heart and Stroke Foundation of Canada
- Alberta Heritage Foundation for Medical Research
The solution structure of Ca2+-bound regulatory domain of cardiac troponin C (cNTnC) in complex with the switch region of troponin I (cTnI(147-163)) and the calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfinamide (W7), has been determined by NMR spectroscopy. The structure reveals that the W7 naphthalene ring interacts with the terminal methyl groups of M47, M60, and M81 as well as aliphatic and aromatic side chains of several other residues in the hydrophobic pocket of cNTnC. The H3 ring proton of W7 also contacts the methyl groups of 1148 and M153 of cTnI(147-163). The N-(6-aminohexyl) tail interacts primarily with the methyl groups of V64 and M81, which are located on the C- and D-helices of cNTnC. Compared to the structure of the cNTnC center dot Ca2+center dot W7 complex (Hoffman, R. M. B. and Sykes, B. D. (2009) Biochemistry 48, 5541-5552), the tail of W7 reorients slightly toward the surface of cNTnC while the ring remains in the hydrophobic pocket. The positively charged -NH3+ group from the tail of W7 repels the positively charged R147 of cTnI(147-163). As a result, the N-terminus of the peptide moves away from cNTnC and the helical content of cTnI(147-163) is diminished, when compared to the structure of cNTnC center dot Ca2+center dot cTnI(147-163) (Li, M. X., Spyracopoulos, L, and Sykes B. D. (1999) Biochemistry 38, 8289-8298). Thus the ternary structure cNTnC center dot Ca2+center dot W7 center dot cTnI(147-163) reported in this study offers an explanation for the similar to 13-fold affinity reduction of cTnI(147-163) for cNTnC center dot Ca2+ in the presence of W7 and provides a structural basis for the inhibitory effect of W7 in cardiac muscle contraction. This generates molecular insight into structural features that are useful for the design of cTnC-specific Ca2+-desensitizing drugs. (C) 2010 Elsevier Ltd. All rights reserved.
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