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PDBsum entry 2d06
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References listed in PDB file
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Key reference
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Title
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The structure of human sult1a1 crystallized with estradiol. An insight into active site plasticity and substrate inhibition with multi-Ring substrates.
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Authors
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N.U.Gamage,
S.Tsvetanov,
R.G.Duggleby,
M.E.Mcmanus,
J.L.Martin.
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Ref.
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J Biol Chem, 2005,
280,
41482-41486.
[DOI no: ]
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PubMed id
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Abstract
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Human SULT1A1 belongs to the supergene family of sulfotransferases (SULTs)
involved in the sulfonation of xeno- and endobiotics. The enzyme is also one of
the SULTs responsible for metabolic activation of mutagenic and carcinogenic
compounds and therefore is implicated in various cancer forms. Further, it is
not well understood how substrate inhibition takes place with rigid fused
multiring substrates such as 17beta-estradiol (E2) at high substrate
concentrations when subcellular fractions or recombinant enzymes are used. To
investigate how estradiol binds to SULT1A1, we co-crystallized SULT1A1 with
sulfated estradiol and the cofactor product, PAP (3'-phosphoadenosine
5'-phosphate). The crystal structure of SULT1A1 that we present here has PAP and
one molecule of E2 bound in a nonproductive mode in the active site. The
structure reveals how the SULT1A1 binding site undergoes conformational changes
to accept fused ring substrates such as steroids. In agreement with previous
reports, the enzyme shows partial substrate inhibition at high concentrations of
E2. A model to explain these kinetics is developed based on the formation of an
enzyme x PAP x E2 dead-end complex during catalysis. This model provides a very
curve. This dead-end
complex is proposed to be that described by the observed structure, where E2 is
bound in a nonproductive mode.
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Figure 2.
FIGURE 2. Comparison of fused ring substrate binding in
SULT1A1, mouse SULT1E1, and human SULT2A1. A, stereoview of E2
binding in the SULT1A1 active site. The noncatalytic substrate
binding mode of SULT1A1 is shown in orange. The O-3 hydroxyl of
E2 can form hydrogen bonds (dotted lines) to PAP and Lys48 (not
shown for clarity). The proposed E2 catalytic orientation
(green) was modeled using GOLD. For comparison, the E2 binding
mode from mouse SULT1E1 is shown (light blue). B,
superimposition of C  traces of
SULT1A1·PAP·pNP (pink) and
SULT1A1·PAP·E2 (green). E2 is shown in orange. A
loop (residues 84-90) that moves to accommodate E2 in the active
site is highlighted in dark blue and indicated by an arrow.
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Figure 4.
FIGURE 4. Stereoview comparing the binding modes of E2
(orange) bound to SULT1A1 and DHEA bound to SULT2A1. The
productive or catalytic orientation of DHEA is shown in green,
and the nonproductive orientation is in black. PAP (light blue)
and the catalytic His108 (gray) of SULT1A1 are shown in a
ball-and-stick representation.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2005,
280,
41482-41486)
copyright 2005.
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