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PDBsum entry 4cll
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References listed in PDB file
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Key reference
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Title
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Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate.
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Authors
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S.Kleinboelting,
A.Diaz,
S.Moniot,
J.Van den heuvel,
M.Weyand,
L.R.Levin,
J.Buck,
C.Steegborn.
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Ref.
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Proc Natl Acad Sci U S A, 2014,
111,
3727-3732.
[DOI no: ]
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PubMed id
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Abstract
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cAMP is an evolutionary conserved, prototypic second messenger regulating
numerous cellular functions. In mammals, cAMP is synthesized by one of 10
homologous adenylyl cyclases (ACs): nine transmembrane enzymes and one soluble
AC (sAC). Among these, only sAC is directly activated by bicarbonate (HCO3(-));
it thereby serves as a cellular sensor for HCO3(-), carbon dioxide (CO2), and pH
in physiological functions, such as sperm activation, aqueous humor formation,
and metabolic regulation. Here, we describe crystal structures of human sAC
catalytic domains in the apo state and in complex with substrate analog,
products, and regulators. The activator HCO3(-) binds adjacent to Arg176, which
acts as a switch that enables formation of the catalytic cation sites. An
anionic inhibitor, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, inhibits
sAC through binding to the active site entrance, which blocks HCO3(-) activation
through steric hindrance and trapping of the Arg176 side chain. Finally, product
complexes reveal small, local rearrangements that facilitate catalysis. Our
results provide a molecular mechanism for sAC catalysis and cellular HCO3(-)
sensing and a basis for targeting this system with drugs.
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