Structural Changes Induced by the Binding of the Calcium
Desensitizer W7 to Cardiac Troponin
Fangze Cai
Peter M. Hwang
Brian D. Sykes
10.1021/acs.biochem.8b00882.s001
https://acs.figshare.com/articles/journal_contribution/Structural_Changes_Induced_by_the_Binding_of_the_Calcium_Desensitizer_W7_to_Cardiac_Troponin/7300295
Compounds that directly
modulate the affinity of the thin filament
calcium regulatory proteins in cardiac muscle have potential for treating
heart disease. A recent “proof of concept” study showed
that the desensitizer W7 can correct hyper-calcium-sensitive sarcomeres
from RCM R193H inhibitory subunit troponin I (cTnI) transgenic mice.
We have determined the high-resolution nuclear magnetic resonance
solution structure of W7 bound to the regulatory domain of calcium
binding subunit troponin C (cNTnC)–cTnI cChimera designed to
represent the key aspects of the cTnC–cTnI interface. The structure
shows that W7 does not perturb the overall structure of the cTnC–cTnI
interface, with the helical structure and position of the cTnI switch
region remaining intact upon W7 binding. The naphthalene ring of W7
sits in the hydrophobic pocket created by the cNTnC–cTnI switch
peptide interface, while the positively charged amine tail extends
into the solvent. The positively charged tail of W7 is in the proximity
of Arg147 of the cTnI switch region, supporting the suggestion that
electrostatic repulsion is an aspect underlying the mechanism of desensitization.
Ser84 (replacing the unique Cys84 in cTnC reported to make a reversible
covalent bond with levosimendan) also contacts W7.
2018-10-30 00:00:00
W 7 binding
Structural Changes Induced
RCM R 193H
aspect
desensitizer W 7
W 7
Calcium Desensitizer W 7
cTnC
cTnI switch region
interface
resonance solution structure
cNTnC
Cardiac Troponin Compounds
calcium binding subunit troponin C