| Autor: |
J. Andrew McCammon, Sandra E. Pineda-Sanabria, Brian D. Sykes, Peter M. Hwang, Steffen Lindert, Fangze Cai, Shorena Gelozia, Monica Li, Frederick G. West |
| Rok vydání: |
2016 |
| Předmět: |
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| Zdroj: |
Biophysical Journal. 110(3) |
| ISSN: |
0006-3495 |
| DOI: |
10.1016/j.bpj.2015.11.2490 |
| Popis: |
Heart failure is the end stage of almost all heart disease, characterized by an inability of the heart to pump enough blood to satisfy the needs of the body. Systolic heart failure is caused by impaired cardiac muscle contraction. In theory, an ideal drug for systolic heart failure would be a positive inotrope, which increases the contractility of heart muscle. However, no positive inotrope has been shown to improve mortality in patients with heart failure. We propose to develop a cardiac troponin activator, which would increase the contractile response of cardiac muscle without increasing the calcium currents entering and exiting the cell.All troponin-modulating drugs studied to-date bind to the interface between the regulatory N-terminal domain of troponin (NTnC) and the troponin I (TnI) switch region, so we developed a cardiac cNTnC-cTnI switch peptide chimera (cChimera) to use for drug screening and structural studies by NMR. We used bepridil as a starting point, because it was a calcium sensitizer with a high affinity for cNTnC-cTnI switch region (KD ∼80 μM). We determined that the two aromatic rings of bepridil accounted for most of its binding affinity, and diphenylamine (DPA) appeared to be an excellent starting compound for further development. We obtained atomic resolution structures of cChimera using solution NMR, both alone and bound to the compound, 3-methyl diphenylamine (3-mDPA). The unsubstituted aromatic ring of 3-mDPA binds to an inner hydrophobic pocket adjacent to the central beta sheet of cNTnC. The methyl-substituted ring binds at the hydrophobic cNTnC-cTnI interface, causing minimal perturbation of cTnI binding. Our work shows that preserving the native interaction between cNTnC-cTnI is key to the development of a high affinity troponin activator. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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