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dc.contributor.authorGamage, NU
dc.contributor.authorTsvetanov, S
dc.contributor.authorDuggleby, RG
dc.contributor.authorMcManus, ME
dc.contributor.authorMartin, JL
dc.date.accessioned2017-09-27T00:07:34Z
dc.date.available2017-09-27T00:07:34Z
dc.date.issued2005
dc.identifier.issn0021-9258
dc.identifier.doi10.1074/jbc.M508289200
dc.identifier.urihttp://hdl.handle.net/10072/347548
dc.description.abstractHuman 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 17β-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·PAP·E2 dead-end complex during catalysis. This model provides a very good quantitative description of the rate versus the [E2] curve. This dead-end complex is proposed to be that described by the observed structure, where E2 is bound in a nonproductive mode.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherThe American Society for Biochemistry and Molecular Biology Inc
dc.relation.ispartofpagefrom41482
dc.relation.ispartofpageto41486
dc.relation.ispartofissue50
dc.relation.ispartofjournalJournal of Biological Chemistry
dc.relation.ispartofvolume280
dc.subject.fieldofresearchChemical sciences
dc.subject.fieldofresearchBiological sciences
dc.subject.fieldofresearchBiochemistry and cell biology not elsewhere classified
dc.subject.fieldofresearchBiomedical and clinical sciences
dc.subject.fieldofresearchcode34
dc.subject.fieldofresearchcode31
dc.subject.fieldofresearchcode310199
dc.subject.fieldofresearchcode32
dc.titleThe structure of human SULT1A1 crystallized with estradiol: An insight into active site plasticity and substrate inhibition with multi-ring substrates
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dc.description.versionVersion of Record (VoR)
gro.rights.copyrightThis research was originally published in Journal of Biological Chemistry (JBC). Niranjali U. Gamage et al, 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 (JBC), Vol. 280 (50), pp. 41482-41486, 2005. Copyright the American Society for Biochemistry and Molecular Biology. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitve version.
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gro.griffith.authorMartin, Jennifer


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