Computational docking of sphingolipids into the regulatory binding site of serine palmitoyltransferase.

Canonically known both for structural contributions to lipid bilayers and roles in cell signaling, the sphingolipids comprise a dynamic, multifaceted class of molecules which are studied to understand cell biology and pathophysiology. All sphingolipids are downstream products of the rate-limiting and initiating enzyme in the de novo sphingolipid synthesis pathway, serine palmitoyltransferase (SPT). SPT activity is strictly regulated. This regulation is accomplished through the ORMDLs, transmembrane polypeptides embedded in the lipid bilayer of the endoplasmic reticulum, which are the regulatory subunits of the SPT complex. Recently the specific mechanism of ORMDL's regulation of SPT was established: ceramide, a downstream product of the de novo biosynthetic pathway, binds directly to a binding site of ORMDL to induce an inhibitory conformational change. Here, we validate a computational docking approach to interrogate the binding efficiency of a range of sphingolipids in the ceramide binding site. We demonstrate that docking poses predicted by this in silico approach reflect experimental data on the efficiency of sphingolipid species to accomplish ORMDL-dependent inhibition of SPT. We propose that this docking analysis will be a valuable complement to experimental tests of compounds that bind to this site to regulate sphingolipid biosynthesis.