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The gate that governs sulfotransferase selectivity.

Ian Cook1, Ting Wang, Steven C Almo

  • 1Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461-1926, USA.

Biochemistry
|December 22, 2012
PubMed
Summary
This summary is machine-generated.

Human sulfotransferases (SULTs) control substrate selection through a nucleotide-induced conformational change. This enzyme isomerization mechanism, observed in SULT2A1 and SULT1A1, regulates active site access for drug and metabolite modification.

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Area of Science:

  • Biochemistry
  • Enzymology
  • Structural Biology

Background:

  • Human cytosolic sulfotransferases (SULTs) catalyze sulfuryl group transfer from PAPS to diverse substrates.
  • Understanding SULT substrate selectivity is crucial for drug metabolism and xenobiotic interactions.
  • Previous studies indicated PAPS binding induces conformational changes in SULT2A1, affecting substrate entry.

Purpose of the Study:

  • To elucidate the molecular basis of nucleotide-induced conformational changes in SULTs that govern substrate selectivity.
  • To investigate the dynamic interplay between the active site cap and nucleotide binding in SULT2A1.
  • To predict and experimentally validate a similar mechanism in SULT1A1.

Main Methods:

  • Utilized equilibrium and nonequilibrium molecular dynamics simulations to explore SULT2A1 dynamics.
  • Performed in silico experiments to assess the role of electrostatic interactions in cap motion.
  • Conducted binding studies with fulvestrant and estradiol to test SULT1A1 substrate selection mechanisms.

Main Results:

  • Molecular dynamics simulations revealed nucleotide-dependent opening and closing of the SULT2A1 active-site cap.
  • The cap's nucleotide and acceptor halves exhibit coupled yet independent motions, explaining isomerization.
  • In silico weakening of interactions demonstrated independent motion of the acceptor half of the cap.
  • Experimental data confirmed that SULT1A1 also undergoes nucleotide-induced isomerization for substrate selection.

Conclusions:

  • Nucleotide binding induces a conformational isomerization in SULTs, controlling active site access and substrate selectivity.
  • This mechanism, involving the dynamic movement of the active-site cap, is conserved between SULT2A1 and SULT1A1.
  • The findings provide critical insights into the molecular basis of SULT enzyme function and drug metabolism.