# Allosteric Mechanisms Triggering Substrate and Cofactor Binding in the SULT1A1 Dimer as Revealed by Molecular Dynamics Simulations

## TL;DR

This study uses simulations to show how dimerization affects the structure and function of the SULT1A1 enzyme, revealing new insights into its allosteric mechanisms.

## Contribution

The study reveals intra- and inter-subunit allosteric effects in SULT1A1 dimers triggered by cofactor and substrate binding.

## Key findings

- Dimerization increases ligand binding gate opening and functional loop fluctuations in SULT1A1.
- Cofactor and substrate binding induce intra- and inter-subunit allosteric effects in the dimer.
- Asymmetric dimer behavior suggests a half-site reactivity mechanism important for large substrates.

## Abstract

Sulfotransferases
(SULTs) are phase II drug-metabolizing enzymes
metabolizing a wide range of endogenous compounds and xenobiotics
including drugs. SULTs form dimers in vivo, and most isoforms share
a conserved dimerization motif. Since it has been shown that the monomers
of the SULT1A1 isoform maintain their activity in vitro, the biological
significance of dimerization remains unclear. To elucidate the mechanism
and the effects of dimerization on the SULT1A1 structure and function,
we performed molecular dynamics (MD) simulations on both the monomer
and dimer form of the enzyme and investigated the effect of cofactor
and substrate binding into the dimer structure and dynamics. Our results
show a clear dynamical effect on the dimerization of the apoenzyme,
resulting in an increase of the ligand binding gate opening and greater
fluctuation of the functional loops of one monomeric subunit. Furthermore,
in the dimer, we uncovered intra- and intersubunit allosteric effects
as a direct consequence of cofactor and the substrate binding, and
we present the corresponding allosteric pathways. Our analyses suggest
that the asymmetric behavior of the dimer in the presence of one PAPS
molecule may reflect a half-site reactivity mechanism, previously
suggested for SULT dimer function, which may be particularly important
for large substrates. Thus, our study shed new light in our understanding
of SULT1A1 structural dynamics and dimerization as related to enzyme
function.