PDBsum entry 2krd

Structural protein

PDB id: 2krd

Contents

Protein chains

89 a.a. *

17 a.a. *

Ligands

WW7

Metals

_CA

* Residue conservation analysis

PDB id:

2krd

Name:

Structural protein

Title:

Solution structure of the regulatory domain of human cardiac troponin c in complex with the switch region of cardiac troponin i and w7

Structure:

Troponin c, slow skeletal and cardiac muscles. Chain: c. Synonym: tn-c. Engineered: yes. Troponin i, cardiac muscle. Chain: i. Synonym: cardiac troponin i. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tnnc1, tnnc. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606

NMR struc:

20 models

Authors:

M.Oleszczuk,I.M.Robertson,M.X.Li,B.D.Sykes

Key ref:

M.Oleszczuk et al. (2010). 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. J Mol Cell Cardiol, 48, 925-933. PubMed id: 20116385

Date:

16-Dec-09 Release date: 16-Feb-10

Protein chain

P63316  (TNNC1_HUMAN) -  Troponin C, slow skeletal and cardiac muscles from Homo sapiens

Seq: 161 a.a.

Struc: 89 a.a.

Protein chain

P19429  (TNNI3_HUMAN) -  Troponin I, cardiac muscle from Homo sapiens

Seq: 210 a.a.

Struc: 17 a.a.

J Mol Cell Cardiol 48:925-933 (2010)

PubMed id: 20116385

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.

M.Oleszczuk, I.M.Robertson, M.X.Li, B.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(2+)*cTnI(147-163) (Li, M. X., Spyracopoulos, L., and Sykes B. D. (1999) Biochemistry 38, 8289-8298). Thus the ternary structure cNTnC*Ca(2+)*W7*cTnI(147-163) reported in this study offers an explanation for the approximately 13-fold affinity reduction of cTnI(147-163) for cNTnC*Ca(2+) in the presence of W7 and provides a structural basis for the inhibitory effect of W7 in cardiac muscle contraction. This generates molecular insight into structural features that are useful for the design of cTnC-specific Ca(2+)-desensitizing drugs.