Solution structure of the regulatory domain of human cardiac troponin C in complex with the switch region of cardiac troponin I and W7: the basis of W7 as an inhibitor of cardiac muscle contraction.

Journal of Molecular and Cellular Cardiology
Marta OleszczukBrian D Sykes

Abstract

The solution structure of Ca(2+)-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 I148 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*Ca(2+)*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 -NH(3)(+) 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*Ca...Continue Reading

References

Sep 1, 1995·Nature Structural Biology·S M GagnéB D Sykes
Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
May 9, 1998·The Journal of Biological Chemistry·Q KleerekoperJ A Putkey
May 3, 2000·Proceedings of the National Academy of Sciences of the United States of America·Y LiC Cohen
Jan 31, 2003·Proteins·Jens P LingeMichael Nilges
Feb 5, 2003·Journal of Magnetic Resonance·Charles D SchwietersG Marius Clore
Feb 16, 2005·Annual Review of Physiology·Tomoyoshi Kobayashi, R John Solaro
Mar 8, 2005·Nature Structural & Molecular Biology·John S AllinghamIvan Rayment
Nov 30, 2005·Biochemistry·Ryan M B HoffmanBrian D Sykes
Jan 19, 2006·Circulation·David A Kass, R John Solaro
Nov 27, 2008·The Journal of Clinical Investigation·Franz BaudenbacherBjörn C Knollmann
Feb 24, 2009·Heart Failure Reviews·John R Teerlink
Mar 12, 2009·Journal of Cardiovascular Pharmacology·Markku S NieminenZoltán Papp
May 8, 2009·Biochemistry·Ryan M B Hoffman, Brian D Sykes

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Citations

Feb 5, 2014·Journal of Muscle Research and Cell Motility·Corrado Poggesi, Carolyn Y Ho
Feb 9, 2016·Journal of Molecular and Cellular Cardiology·Sandra E Pineda-SanabriaBrian D Sykes
Aug 31, 2010·Journal of Molecular and Cellular Cardiology·Ian M RobertsonBrian D Sykes
Apr 18, 2015·Nature Reviews. Drug Discovery·Peter M Hwang, Brian D Sykes
May 21, 2016·American Journal of Physiology. Heart and Circulatory Physiology·Brian R ThompsonJoseph M Metzger
Mar 12, 2021·Journal of Medicinal Chemistry·Monica X LiBrian D Sykes
Jul 8, 2020·ACS Chemical Biology·Fangze CaiBrian D Sykes
Jul 8, 2020·Journal of Chemical Information and Modeling·William H ColdrenSteffen Lindert
Aug 14, 2020·Journal of Molecular and Cellular Cardiology·Anthony D VetterJoseph M Metzger
Mar 24, 2021·The Journal of Clinical Investigation·Martijn van de LochtCoen Ac Ottenheijm
Jun 12, 2021·The Journal of Physical Chemistry. B·Kalyan ImmadisettyPeter M Kekenes-Huskey
Jul 11, 2014·ACS Chemical Biology·Sandra E Pineda-SanabriaBrian D Sykes
Sep 18, 2021·ACS Medicinal Chemistry Letters·Fangze CaiBrian D Sykes

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