Darrah, Kristie; Wang, Ting; Cook, Ian; Cacace, Mary; Deiters, Alexander; Leyh, Thomas S. published the artcile< Allosteres to regulate neurotransmitter sulfonation>, Formula: C7H6BrNO, the main research area is SULT1A3 allosteric inhibitor catecholamine 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.
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 ab initio as a function of core substituents and used to design and synthesize a series of inhibitors intended to progressively stabilize the cap and slow turnover. The inhibitors bound tightly (34 nm to 7.4μm) and exhibited progressive inhibition. The cap-stabilizing effects of the inhibitors were exptl. determined and agreed remarkably well with the theor. predictions. These studies establish a reliable heuristic for the design of SULT1A3 allosteric inhibitors and demonstrate that the free-energy changes of a small, dynamic loop that is critical for SULT substrate selection and turnover can be calculated accurately.
Journal of Biological Chemistry published new progress about Allosterism. 29124-57-0 belongs to class bromides-buliding-blocks, and the molecular formula is C7H6BrNO, Formula: C7H6BrNO.
Referemce:
Bromide – Wikipedia,
bromide – Wiktionary