4GRA

Crystal structure of SULT1A1 bound with PAP

4GRA の概要

• エントリーDOI: 10.2210/pdb4gra/pdb
• 分子名称: Sulfotransferase 1A1, ADENOSINE-3'-5'-DIPHOSPHATE (3 entities in total)
• 機能のキーワード: sulfotransferase, estradiol, hormone regulation, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P50225
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70144.03

構造登録者

Kim, J.,Cook, I.,Wang, T.,Falany, C.N.,Leyh, T.S.,Almo, S.C. (登録日: 2012-08-24, 公開日: 2013-01-16, 最終更新日: 2023-09-13)

主引用文献

Cook, I.,Wang, T.,Almo, S.C.,Kim, J.,Falany, C.N.,Leyh, T.S.
The gate that governs sulfotransferase selectivity.
Biochemistry, 52:415-424, 2013

PubMed Abstract: Human cytosolic sulfotransferases (SULTs) transfer the sulfuryl moiety (-SO(3)) from activated sulfate [3'-phosphoadenosine 5'-phosphosulfate (PAPS)] to the hydroxyls and primary amines of numerous metabolites, drugs, and xenobiotics. Receipt of the sulfuryl group often radically alters acceptor-target interactions. How these enzymes select particular substrates from the hundreds of candidates in a complex cytosol remains an important question. Recent work reveals PAPS binding causes SULT2A1 to undergo an isomerization that controls selectivity by constricting the opening through which acceptors must pass to enter the active site. The enzyme maintains an affinity for large substrates by isomerizing between the open and closed states with nucleotide bound. Here, the molecular basis of the nucleotide-induced closure is explored in equilibrium and nonequilibrium molecular dynamics simulations. The simulations predict that the active-site "cap," which covers both the nucleotide and acceptor binding sites, opens and closes in response to nucleotide. The cap subdivides into nucleotide and acceptor halves whose motions, while coupled, exhibit an independence that can explain the isomerization. In silico weakening of electrostatic interactions between the cap and base of the active site causes the acceptor half of the cap to open and close while the nucleotide lid remains shut. Simulations predict that SULT1A1, the most abundant SULT in human liver, will utilize a similar selection mechanism. This prediction is tested using fulvestrant, an anti-estrogen too large to pass through the closed pore, and estradiol, which is not restricted by closure. Equilibrium and pre-steady-state binding studies confirm that SULT1A1 undergoes a nucleotide-induced isomerzation that controls substrate selection.

PubMed: 23256751
DOI: 10.1021/bi301492j

実験手法

X-RAY DIFFRACTION (2.56 Å)