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PDBsum entry 1kux
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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X-Ray crystallographic studies of serotonin n-Acetyltransferase catalysis and inhibition.
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Authors
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E.Wolf,
J.De angelis,
E.M.Khalil,
P.A.Cole,
S.K.Burley.
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Ref.
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J Mol Biol, 2002,
317,
215-224.
[DOI no: ]
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PubMed id
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Abstract
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The structure of serotonin N-acetyltransferase (also known as arylalkylamine
N-acetyltransferase; AANAT) bound to a potent bisubstrate analog inhibitor has
been determined at 2.0 A resolution using a two-edge (Se, Br) multiwavelength
anomalous diffraction (MAD) experiment. This acetyl-CoA dependent enzyme is a
member of the GCN5-related family of N-acetyltransferases (GNATs), which share
four conserved sequence motifs (A-D). In serotonin N-acetyltransferase, motif A
adopts an alpha/beta conformation characteristic of the phylogenetically
invariant cofactor binding site seen in all previously characterized GNATs.
Motif B displays a significantly lower level of conservation among family
members, giving rise to a novel alpha/beta structure for the serotonin binding
slot. Utilization of a brominated CoA-S-acetyl-tryptamine-bisubstrate analog
inhibitor and the MAD method permitted conclusive identification of two
radically different conformations for the tryptamine moiety in the catalytic
site (cis and trans). A second high-resolution X-ray structure of the enzyme
bound to a bisubstrate analog inhibitor, with a longer tether between the
acetyl-CoA and tryptamine moieties, demonstrates only the trans conformation.
Given a previous proposal that AANAT can catalyze an alkyltransferase reaction
in a conformationally altered active site relative to its acetyltransferase
activity, it is possible that the two conformations of the bisubstrate analog
observed crystallographically correspond to these alternative reaction pathways.
Our findings may ultimately lead to the design of analogs with improved AANAT
inhibitory properties for in vivo applications.
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Figure 1.
Figure 1. Enzyme-catalyzed reactions and inhibitors for
serotonin N-acetyltransferase. (a) Serotonin
N-acetyltransferase-catalyzed reaction between serotonin and
acetyl-CoA. (b) Alkyl transfer reaction between CoASH and
N-bromoacetyltryptamine. (c) Bisubstrate analog inhibitors 1, 2,
and 3.
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Figure 4.
Figure 4. Overlay of compounds 1 and 3 in the active site
of AANAT. Left: a stereodrawing of compounds 1 (green) and 3
(red) drawn as atomic stick figures with selected atoms labeled.
Right: the atomic numbering scheme for the tryptamine moieties
of compounds 1, 2, and 3.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2002,
317,
215-224)
copyright 2002.
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