2KFX

Structure of the N-terminal domain of human cardiac troponin C bound to calcium ion and to the inhibitor W7

Summary for 2KFX

• Entry DOI: 10.2210/pdb2kfx/pdb
• NMR Information: BMRB: 16190
• Descriptor: Troponin C, slow skeletal and cardiac muscles, CALCIUM ION, N-(6-AMINOHEXYL)-5-CHLORO-1-NAPHTHALENESULFONAMIDE (3 entities in total)
• Functional Keywords: calcium regulation, striated muscle, cardiac, troponin, w7, cardiotonic drugs, acetylation, calcium, cardiomyopathy, disease mutation, muscle protein, polymorphism, metal binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 10419.12

Authors

Hoffman, R.M.B.,Sykes, B.D. (deposition date: 2009-02-28, release date: 2009-06-09, Last modification date: 2024-05-22)

Primary citation

Hoffman, R.M.,Sykes, B.D.
Structure of the inhibitor W7 bound to the regulatory domain of cardiac troponin C.
Biochemistry, 48:5541-5552, 2009

PubMed Abstract: The calmodulin antagonist W7 binds to troponin C in the presence of Ca(2+) and inhibits striated muscle contraction. This study integrates multiple data into the structure of the regulatory domain of human cardiac troponin C (cNTnC) bound to Ca(2+) and W7. The protein-W7 interface is defined through a three-dimensional {(1)H,(13)C}-edited-{(1)H,(12)C}-detected NOESY NMR experiment, and other aspects of the structure are modeled as perturbations to previously known coordinates and restraints. The structure determination protocol optimizes the protein-W7 contacts prior to the introduction of protein-W7 steric interactions or conformational changes in the protein. The structure determination protocol gives families of conformers that all have an optimal docking as assessed by satisfaction of the target function. The structure supports the previously proposed troponin I blocking mechanism for the activity of W7 in striated muscle and suggests a role for the flexible tail of W7 in stabilization of the bound state. This clarifies the structure-activity relationships of W7 and implicates an electrostatically mediated component of activity in common analogues of W7, including the antipsychotic trifluoroperazine and the cardiotonic levosimendan.

PubMed: 19419198
DOI: 10.1021/bi9001826

Experimental method

SOLUTION NMR