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PDBsum entry 2ctn
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Calcium-binding protein
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PDB id
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2ctn
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References listed in PDB file
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Key reference
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Title
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Structure of cardiac muscle troponin c unexpectedly reveals a closed regulatory domain.
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Authors
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S.K.Sia,
M.X.Li,
L.Spyracopoulos,
S.M.Gagné,
W.Liu,
J.A.Putkey,
B.D.Sykes.
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Ref.
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J Biol Chem, 1997,
272,
18216-18221.
[DOI no: ]
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PubMed id
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Abstract
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The regulation of cardiac muscle contraction must differ from that of skeletal
muscles to effect different physiological and contractile properties. Cardiac
troponin C (TnC), the key regulator of cardiac muscle contraction, possesses
different functional and Ca2+-binding properties compared with skeletal TnC and
features a Ca2+-binding site I, which is naturally inactive. The structure of
cardiac TnC in the Ca2+-saturated state has been determined by nuclear magnetic
resonance spectroscopy. The regulatory domain exists in a "closed"
conformation even in the Ca2+-bound (the "on") state, in contrast to
all predicted models and differing significantly from the calcium-induced
structure observed in skeletal TnC. This structure in the Ca2+-bound state, and
its subsequent interaction with troponin I (TnI), are crucial in determining the
specific regulatory mechanism for cardiac muscle contraction. Further, it will
allow for an understanding of the action of calcium-sensitizing drugs, which
bind to cardiac TnC and are known to enhance the ability of cardiac TnC to
activate cardiac muscle contraction.
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Figure 1.
Fig. 1. Structure of Ca^2+-saturated cardiac TnC as
determined in this study (sequence starts at Ala^2 and ends at
Val161). The  -helices
are approximately as follows: N-helix (residues 6-10), A-helix
(14-28), B-helix (38-48), C-helix (54-64), D-helix (74-83),
E-helix (95-103), F-helix (114-123), G-helix (130-140), H-helix
(150-158). The antiparallel  -sheets
connect residues 35-37 and 71-73 in the N-domain, and residues
111-113 and 147-149^ in the C-domain. All regions of the
molecule are well defined, with the exceptions of the following
regions: the N- and C-terminal residues (2-4 and 159-161),
residues 30-33 of defunct site I, residues 49-55 of the B-C
linker, residues 66-68 of site II, the^ central linker (86-94),
and residues 125-129 of the F-G linker. Stereo views of the
superposition of 30 structures for the regulatory N-domain
(residues 5-84, A) and the structural C-domain (95-158, B) are
shown. Positions of the Ca^2+ ions are indicated by gray
spheres. This figure was prepared^ with the program RASTER3D
(37).
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Figure 4.
Fig. 4. Comparison of the surface structures of the
regulatory N-domains of 4Ca·skeletal TnC (NMR) (A),
3Ca·cardiac TnC (NMR) (B), and 3Ca·cardiac TnC
(model, Ref. 9) (C), displayed in the same^ orientation as Fig.
1A. Side chains of hydrophobic residues (Ala, Ile, Leu, Met,
Pro, Phe, Tyr, and Val) are shown in yellow, negatively charged
residues (Asp and Glu) in red, positively charged^ residues (Arg
and Lys) in blue, and all other residues in gray. The major
hydrophobic pocket of 3Ca·cardiac TnC involves residues
Phe^20, Phe^24, Leu48, Phe^74, Phe^77, Leu78, Met81, and Met85,
and residues Ile^36, Leu41, Met45, Leu57, Met60, Ile^61, Val64,
Val72, and Met80. Other hydrophobic contacts are also observed
from Phe^20, Ala^23, and Phe^27 of the A-helix to Val44, Met47,
and Leu48 of the B-helix, and from Ala^8, Val9, and Leu12 of the
N-helix to Leu78, Val79, and Val82 of the D-helix. This figure
was generated using the program GRASP (38).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(1997,
272,
18216-18221)
copyright 1997.
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