Allosteres to regulate neurotransmitter sulfonation.
SULT1A3
allosteric regulation
allostery
catecholamine
dopamine
enzyme inhibitor
enzyme kinetics
enzyme mechanism
enzyme structure
epinephrine
inhibition
mechanism
neurotransmitter
norepinephrine
nuclear magnetic resonance (NMR)
serotonin
spin label
sulfotransferase
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
15 02 2019
15 02 2019
Historique:
received:
31
10
2018
revised:
12
12
2018
pubmed:
14
12
2018
medline:
30
4
2019
entrez:
15
12
2018
Statut:
ppublish
Résumé
Catecholamine neurotransmitter levels in the synapses of the brain shape human disposition-cognitive flexibility, aggression, depression, and reward seeking-and manipulating these levels is a major objective of the pharmaceutical industry. Certain neurotransmitters are extensively sulfonated and inactivated by human sulfotransferase 1A3 (SULT1A3). To our knowledge, sulfonation as a therapeutic means of regulating transmitter activity has not been explored. Here, we describe the discovery of a SULT1A3 allosteric site that can be used to inhibit the enzyme. The structure of the new site is determined using spin-label-triangulation NMR. The site forms a cleft at the edge of a conserved ∼30-residue active-site cap that must open and close during the catalytic cycle. Allosteres anchor into the site via π-stacking interactions with two residues that sandwich the planar core of the allostere and inhibit the enzyme through cap-stabilizing interactions with substituents attached to the core. Changes in cap free energy were calculated
Identifiants
pubmed: 30545938
pii: S0021-9258(20)39985-3
doi: 10.1074/jbc.RA118.006511
pmc: PMC6378965
doi:
Substances chimiques
Neurotransmitter Agents
0
Spin Labels
0
Arylsulfotransferase
EC 2.8.2.1
monoamine-sulfating phenol sulfotransferase
EC 2.8.2.1
Banques de données
PDB
['2A3R']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2293-2301Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM112728
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM121849
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM127144
Pays : United States
Informations de copyright
© 2019 Darrah et al.
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