2D06

Human Sult1A1 Complexed With Pap and estradiol

Summary for 2D06

• Entry DOI: 10.2210/pdb2d06/pdb
• Descriptor: Sulfotransferase 1A1, ADENOSINE-3'-5'-DIPHOSPHATE, ESTRADIOL, ... (4 entities in total)
• Functional Keywords: sult 1a1, pap, estradiol, substrarte inhibition, dead end complex, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P50225
• Total number of polymer chains: 2
• Total formula weight: 69839.78

Authors

Gamage, N.U.,Tsvetanov, S.,Duggleby, R.G.,McManus, M.E.,Martin, J.L. (deposition date: 2005-07-25, release date: 2005-10-25, Last modification date: 2023-10-25)

Primary citation

Gamage, N.U.,Tsvetanov, S.,Duggleby, R.G.,McManus, M.E.,Martin, J.L.
The structure of human SULT1A1 crystallized with estradiol. An insight into active site plasticity and substrate inhibition with multi-ring substrates
J.Biol.Chem., 280:41482-41486, 2005

PubMed Abstract: 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 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.

PubMed: 16221673
DOI: 10.1074/jbc.M508289200

Experimental method

X-RAY DIFFRACTION (2.3 Å)