PDBsum entry 1ih0

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Contractile protein PDB id
Protein chain
71 a.a. *
_CA ×2
* Residue conservation analysis
PDB id:
Name: Contractile protein
Title: Structure of thE C-domain of human cardiac troponin c in complex with ca2+ sensitizer emd 57033
Structure: Troponin c, slow skeletal and cardiac muscles. Chain: a. Fragment: c-terminal domain (residues 91-161). Synonym: tn-c. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ctnc. Expressed in: escherichia coli. Expression_system_taxid: 562.
NMR struc: 30 models
Authors: X.Wang,M.X.Li,L.Spyracopoulos,N.Beier,M.Chandra,R.J.Solaro, B.D.Sykes
Key ref:
X.Wang et al. (2001). Structure of the C-domain of human cardiac troponin C in complex with the Ca2+ sensitizing drug EMD 57033. J Biol Chem, 276, 25456-25466. PubMed id: 11320096 DOI: 10.1074/jbc.M102418200
18-Apr-01     Release date:   10-Oct-01    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P63316  (TNNC1_HUMAN) -  Troponin C, slow skeletal and cardiac muscles
161 a.a.
71 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     calcium ion binding     1 term  


DOI no: 10.1074/jbc.M102418200 J Biol Chem 276:25456-25466 (2001)
PubMed id: 11320096  
Structure of the C-domain of human cardiac troponin C in complex with the Ca2+ sensitizing drug EMD 57033.
X.Wang, M.X.Li, L.Spyracopoulos, N.Beier, M.Chandra, R.J.Solaro, B.D.Sykes.
Ca(2+) binding to cardiac troponin C (cTnC) triggers contraction in heart muscle. In heart failure, myofilaments response to Ca(2+) are often altered and compounds that sensitize the myofilaments to Ca(2+) possess therapeutic value in this syndrome. One of the most potent and selective Ca(2+) sensitizers is the thiadiazinone derivative EMD 57033, which increases myocardial contractile function both in vivo and in vitro and interacts with cTnC in vitro. We have determined the NMR structure of the 1:1 complex between Ca(2+)-saturated C-domain of human cTnC (cCTnC) and EMD 57033. Favorable hydrophobic interactions between the drug and the protein position EMD 57033 in the hydrophobic cleft of the protein. The drug molecule is orientated such that the chiral group of EMD 57033 fits deep in the hydrophobic pocket and makes several key contacts with the protein. This stereospecific interaction explains why the (-)-enantiomer of EMD 57033 is inactive. Titrations of the cCTnC.EMD 57033 complex with two regions of cardiac troponin I (cTnI(34-71) and cTnI(128-147)) reveal that the drug does not share a common binding epitope with cTnI(128-147) but is completely displaced by cTnI(34-71). These results have important implications for elucidating the mechanism of the Ca(2+) sensitizing effect of EMD 57033 in cardiac muscle contraction.
  Selected figure(s)  
Figure 2.
Fig. 2. A, the solution structure of the cCTnC·EMD 57033 complex. The backbones (N, C , and C') of a family of 30 structures are shown in blue. The assembly of EMD 57033 structures is shown in red. The Ca^2+ ions are shown as green spheres. B, the ribbon representation of the cCTnC·EMD 57033 complex. The protein is shown in dark red and Ca^2+ ions are shown as cyan spheres. The thiadiazinone functional group of the drug is colored in blue; the tetrahydroquinolyl group of the drug is colored in gold; and the dimethoxybenzoyl group is shown in gray. C, molecular surface of cCTnC in the cCTnC·EMD 57033 complex. The side chain atoms of hydrophobic residues (Ala, Ile, Leu, Met, Phe, and Val) are shown in yellow. Negatively charged residues (Asp and Glu) in red, positively charged residues (Arg and Lys) in blue. Polar residues (Ser, Thr, and Tyr) are shown in cyan. EMD 57033 is embedded in the hydrophobic cleft of the protein. The orientation of the complex is the same as in B. C was created with the program GRASP (47).
Figure 5.
Fig. 5. A, the backbone overlay of cCTnC in the cCTnC·EMD 57033 complex ( dark red) and the free C-domain of cTnC (green), PDB accession code 1AJ4. The two Ca^2+ ions are shown as cyan-colored spheres. The three units of the drug are colored in the same scheme as Fig. 2B. Note the slight opening of helix E and F as well as the unwinding of the C-terminal helix. B, the backbone overlay of cCTnC in the cCTnC·EMD 57033 complex (dark red) with the C-domain of skeletal TnC (purple), bound to sTnI[1-47] (light green), PDB accession code 1A2X. The Ca^2+ ions and EMD 57033 are colored in the same scheme as in A. The overlay shows that the binding of EMD 57033 to cCTnC mimics the binding of sTnI[1-47] to sCTnC.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2001, 276, 25456-25466) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19798510 J.Ochala, P.J.Radell, L.I.Eriksson, and L.Larsson (2010).
EMD 57033 partially reverses ventilator-induced diaphragm muscle fibre calcium desensitisation.
  Pflugers Arch, 459, 475-483.  
20977454 N.Tadano, C.K.Du, F.Yumoto, S.Morimoto, M.Ohta, M.F.Xie, K.Nagata, D.Y.Zhan, Q.W.Lu, Y.Miwa, F.Takahashi-Yanaga, M.Tanokura, I.Ohtsuki, and T.Sasaguri (2010).
Biological actions of green tea catechins on cardiac troponin C.
  Br J Pharmacol, 161, 1034-1043.  
19542563 I.M.Robertson, M.X.Li, and B.D.Sykes (2009).
Solution structure of human cardiac troponin C in complex with the green tea polyphenol, (-)-epigallocatechin 3-gallate.
  J Biol Chem, 284, 23012-23023.
PDB code: 2kdh
18570382 I.M.Robertson, O.K.Baryshnikova, M.X.Li, and B.D.Sykes (2008).
Defining the binding site of levosimendan and its analogues in a regulatory cardiac troponin C-troponin I complex.
  Biochemistry, 47, 7485-7495.  
18386050 J.R.Pinto, T.Veltri, and M.M.Sorenson (2008).
Modulation of troponin C affinity for the thin filament by different cross-bridge states in skinned skeletal muscle fibers.
  Pflugers Arch, 456, 1177-1187.  
18162171 M.X.Li, I.M.Robertson, and B.D.Sykes (2008).
Interaction of cardiac troponin with cardiotonic drugs: a structural perspective.
  Biochem Biophys Res Commun, 369, 88-99.  
17268593 U.Ryde (2007).
Accurate metal-site structures in proteins obtained by combining experimental data and quantum chemistry.
  Dalton Trans, (), 607-625.  
15772750 Y.W.Hsiao, T.Drakenberg, and U.Ryde (2005).
NMR structure determination of proteins supplemented by quantum chemical calculations: detailed structure of the Ca2+ sites in the EGF34 fragment of protein S.
  J Biomol NMR, 31, 97.  
15201148 M.P.Sumandea, E.M.Burkart, T.Kobayashi, P.P.De Tombe, and R.J.Solaro (2004).
Molecular and integrated biology of thin filament protein phosphorylation in heart muscle.
  Ann N Y Acad Sci, 1015, 39-52.  
15711886 M.X.Li, X.Wang, and B.D.Sykes (2004).
Structural based insights into the role of troponin in cardiac muscle pathophysiology.
  J Muscle Res Cell Motil, 25, 559-579.  
12720486 M.Endoh (2003).
The therapeutic potential of novel cardiotonic agents.
  Expert Opin Investig Drugs, 12, 735-750.  
14661957 M.X.Li, X.Wang, D.A.Lindhout, N.Buscemi, J.E.Van Eyk, and B.D.Sykes (2003).
Phosphorylation and mutation of human cardiac troponin I deferentially destabilize the interaction of the functional regions of troponin I with troponin C.
  Biochemistry, 42, 14460-14468.  
12562319 S.A.Doggrell (2003).
Is levosimendan a breakthrough in the development of positive inotropes?
  Expert Opin Pharmacother, 4, 289-292.  
12083991 S.A.Doggrell, and L.Brown (2002).
Present and future pharmacotherapy for heart failure.
  Expert Opin Pharmacother, 3, 915-930.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.