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PDBsum entry 4oz2
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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 structure of human soluble adenylate cyclase reveals a distinct, Highly flexible allosteric bicarbonate binding pocket.
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Authors
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S.M.Saalau-Bethell,
V.Berdini,
A.Cleasby,
M.Congreve,
J.E.Coyle,
V.Lock,
C.W.Murray,
M.A.O'Brien,
S.J.Rich,
T.Sambrook,
M.Vinkovic,
J.R.Yon,
H.Jhoti.
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Ref.
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Chemmedchem, 2014,
9,
823-832.
[DOI no: ]
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PubMed id
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Abstract
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Soluble adenylate cyclases catalyse the synthesis of the second messenger cAMP
through the cyclisation of ATP and are the only known enzymes to be directly
activated by bicarbonate. Here, we report the first crystal structure of the
human enzyme that reveals a pseudosymmetrical arrangement of two catalytic
domains to produce a single competent active site and a novel discrete
bicarbonate binding pocket. Crystal structures of the apo protein, the protein
in complex with α,β-methylene adenosine 5'-triphosphate (AMPCPP) and calcium,
with the allosteric activator bicarbonate, and also with a number of inhibitors
identified using fragment screening, all show a flexible active site that
undergoes significant conformational changes on binding of ligands. The
resulting nanomolar-potent inhibitors that were developed bind at both the
substrate binding pocket and the allosteric site, and can be used as chemical
probes to further elucidate the function of this protein.
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