6MV3

NMR structure of the cNTnC-cTnI chimera bound to calcium desensitizer W7

Summary for 6MV3

• Entry DOI: 10.2210/pdb6mv3/pdb
• NMR Information: BMRB: 30529
• Descriptor: Troponin C, slow skeletal and cardiac muscles,Troponin I, cardiac muscle chimera, CALCIUM ION, N-(6-AMINOHEXYL)-5-CHLORO-1-NAPHTHALENESULFONAMIDE (3 entities in total)
• Functional Keywords: cardiac troponin, calcium binding protein, ef hand, metal binding protein, calcium desensitizer, w7
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 14567.07

Authors

Cai, F.,Hwang, P.M.,Sykes, B.D. (deposition date: 2018-10-24, release date: 2018-11-14, Last modification date: 2024-05-15)

Primary citation

Cai, F.,Hwang, P.M.,Sykes, B.D.
Structural Changes Induced by the Binding of the Calcium Desensitizer W7 to Cardiac Troponin.
Biochemistry, 57:6461-6469, 2018

PubMed Abstract: 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.

PubMed: 30376637
DOI: 10.1021/acs.biochem.8b00882

Experimental method

SOLUTION NMR