PDBsum entry 2d06

Transferase

PDB id: 2d06

Contents

Protein chain

288 a.a. *

Ligands

A3P ×2

EST ×2

Waters ×119

* Residue conservation analysis

PDB id:

2d06

Name:

Transferase

Title:

Human sult1a1 complexed with pap and estradiol

Structure:

Sulfotransferase 1a1. Chain: a, b. Synonym: sult1a1, phenol sulfotransferase 1, aryl sulfotransferase 1, phenol-sulfating phenol sulfotransferase 1, p- pst 1, thermostable phenol sulfotransferase, ts-pst, hast1/hast2, st1a3. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Tissue: liver. Gene: sult1a1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.30Å R-factor: 0.217 R-free: 0.283

Authors:

N.U.Gamage,S.Tsvetanov,R.G.Duggleby,M.E.Mcmanus,J.L.Martin

Key ref:

N.U.Gamage et al. (2005). 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. PubMed id: 16221673 DOI: 10.1074/jbc.M508289200

Date:

25-Jul-05 Release date: 25-Oct-05

Protein chains

P50225  (ST1A1_HUMAN) -  Sulfotransferase 1A1 from Homo sapiens

Seq: 295 a.a.

Struc: 288 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.8.2.1 - aryl sulfotransferase.
• Reaction: a phenol + 3'-phosphoadenylyl sulfate = an aryl sulfate + adenosine 3',5'-bisphosphate + H⁺

phenol + 3'-phosphoadenylyl sulfate = aryl sulfate (Bound ligand (Het Group name = A3P) corresponds exactly) + adenosine 3',5'-bisphosphate + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1074/jbc.M508289200

J Biol Chem 280:41482-41486 (2005)

PubMed id: 16221673

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

N.U.Gamage, S.Tsvetanov, R.G.Duggleby, M.E.McManus, J.L.Martin.

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 curve. This dead-end complex is proposed to be that described by the observed structure, where E2 is bound in a nonproductive mode.

Selected figure(s)

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.

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.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 41482-41486) copyright 2005.

Figures were selected by the author.