# Structural dynamics of sphingosine kinase 1 regulation and inhibition

## TL;DR

This study reveals how sphingosine kinase 1 changes shape during activity and inhibition, offering insights for better drug design.

## Contribution

The paper identifies a new catalytic intermediate and a dynamic dimerization mechanism in SK1 regulation.

## Key findings

- Phosphorylation of Ser225 triggers structural changes that activate SK1.
- PF-543 inhibits SK1 by stabilizing an inactive conformation and restricting loop dynamics.
- SK1 forms functional dimers stabilized by ligands or membranes, revealing a multilayered regulatory mechanism.

## Abstract

Sphingosine kinase 1 (SK1) produces sphingosine-1-phosphate, a bioactive lipid implicated in cancer progression and other diseases. Despite its clinical relevance, the structural and dynamic basis of SK1 regulation and inhibition remains poorly understood. Using an integrated spectroscopic and computational approach, we uncover conformational transitions that govern substrate entry, catalysis, and inhibitor binding. Phosphorylation of Ser225 triggers regulatory loop rearrangements and salt bridge reshuffling, priming SK1 for membrane engagement and catalytic activity. We identify a previously uncharacterized catalytic intermediate featuring a distinct conformation with a highly dynamic lipid-binding loop 1 (LBL-1), sensitive to potent inhibitors such as PF-543. This inhibitor locks SK1 in an inactive state by restricting LBL-1 dynamics and globally stabilizing a non-catalytic conformation. Notably, SK1 forms functionally distinct dimers stabilized by ligand or membrane interactions, revealing a dynamic, multilayered regulatory mechanism governed by structural flexibility. These findings define a novel inhibitory mechanism and offer a structural framework for developing next-generation SK1-targeted therapeutics.