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PDBsum entry 3e8a
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Lyase/lyase inhibitor
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PDB id
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3e8a
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Contents |
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190 a.a.
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188 a.a.
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328 a.a.
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References listed in PDB file
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Key reference
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Title
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Structural basis for inhibition of mammalian adenylyl cyclase by calcium.
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Authors
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T.C.Mou,
N.Masada,
D.M.Cooper,
S.R.Sprang.
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Ref.
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Biochemistry, 2009,
48,
3387-3397.
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PubMed id
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Abstract
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Type V and VI mammalian adenylyl cyclases (AC5, AC6) are inhibited by Ca(2+) at
both sub- and supramicromolar concentration. This inhibition may provide
feedback in situations where cAMP promotes opening of Ca(2+) channels, allowing
fine control of cardiac contraction and rhythmicity in cardiac tissue where AC5
and AC6 predominate. Ca(2+) inhibits the soluble AC core composed of the C1
domain of AC5 (VC1) and the C2 domain of AC2 (IIC2). As observed for holo-AC5,
inhibition is biphasic, showing "high-affinity" (K(i) = approximately 0.4
microM) and "low-affinity" (K(i) = approximately 100 microM) modes of
inhibition. At micromolar concentration, Ca(2+) inhibition is nonexclusive with
respect to pyrophosphate (PP(i)), a noncompetitive inhibitor with respect to
ATP, but at >100 microM Ca(2+), inhibition appears to be exclusive with
respect to PP(i). The 3.0 A resolution structure of
Galphas.GTPgammaS/forskolin-activated VC1:IIC2 crystals soaked in the presence
of ATPalphaS and 8 microM free Ca(2+) contains a single, loosely coordinated
metal ion. ATP soaked into VC1:IIC2 crystals in the presence of 1.5 mM Ca(2+) is
not cyclized, and two calcium ions are observed in the 2.9 A resolution
structure of the complex. In both of the latter complexes VC1:IIC2 adopts the
"open", catalytically inactive conformation characteristic of the apoenzyme, in
contrast to the "closed", active conformation seen in the presence of ATP
analogues and Mg(2+) or Mn(2+). Structures of the pyrophosphate (PP(i)) complex
with 10 mM Mg(2+) (2.8 A) or 2 mM Ca(2+) (2.7 A) also adopt the open
conformation, indicating that the closed to open transition occurs after cAMP
release. In the latter complexes, Ca(2+) and Mg(2+) bind only to the
high-affinity "B" metal site associated with substrate/product stabilization.
Ca(2+) thus stabilizes the inactive conformation in both ATP- and PP(i)-bound
states.
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