The structure of human SULT1A1 crystallized with estradiol: An insight into active site plasticity and substrate inhibition with multi-ring substrates

Gamage, N. U., Tsvetanov, S., Duggleby, R. G., McManus, M. E. and Martin, J. L. (2005) The structure of human SULT1A1 crystallized with estradiol: An insight into active site plasticity and substrate inhibition with multi-ring substrates. Journal of Biological Chemistry, 280 50: 41482-41486. doi:10.1074/jbc.M508289200

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Author Gamage, N. U.
Tsvetanov, S.
Duggleby, R. G.
McManus, M. E.
Martin, J. L.
Title The structure of human SULT1A1 crystallized with estradiol: An insight into active site plasticity and substrate inhibition with multi-ring substrates
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2005
Sub-type Article (original research)
DOI 10.1074/jbc.M508289200
Open Access Status File (Publisher version)
Volume 280
Issue 50
Start page 41482
End page 41486
Total pages 5
Place of publication Bethesda, MD
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Subject 1115 Pharmacology and Pharmaceutical Sciences
Abstract Human SULT1A1 belongs to the supergene family of sulfotransferases (SULTs) involved in the sulfonation of xeno- and endo-biotics. 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, how substrate inhibition takes place with rigid fused multi-ring substrates such as E2 at high substrate concentrations when subcellular fractions or recombinant enzymes are used is not well understood. To investigate how estradiol binds to SULT1A1, we co-crystallized SULT1A1 with the cofactor product PAP (3’-phosphoadenosine 5’-phosphate) and sulfated estradiol (E2S). The crystal structure of SULT1A1 that we present here has PAP and one molecule of E2 bound in a non-productive 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:PAP:E2 dead-end complex during catalysis. This model provides a very good quantitative description of the rate versus [E2] curve. This dead-end complex is proposed to be that described by the observed structure, where E2 is bound in a non-productive mode.
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Created: Tue, 11 Apr 2006, 23:43:01 EST