Structural analysis of the inhibition of APRIL by TACI and BCMA through molecular dynamics simulations

APRIL (a proliferation-inducing ligand) is a member of the tumour necrosis factor (TNF) superfamily that binds the receptors (TNFRs) TACI and BCMA. Since it was discovered, a great amount of evidence has been reported about the involvement of APRIL in autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS) and multiple sclerosis (MS). In addition, an important role of APRIL has been described in different types of tumour cell lines and in a variety of primary tumour tissues where, in contrast with the normal ones, high mRNA levels have been detected. Accordingly, the design of compounds mimicking the inhibition of APRIL by its receptors appears to be a promising way to treat autoimmune and cancer diseases. As a first step to achieve these goals and in order to better understand the key interactions involved in these systems, we report a structural analysis of the inhibition of human and murine APRIL by its human receptors TACI and BCMA obtained by molecular dynamics simulations. Although most of the key interactions can be obtained from the existing experimental information, new described interactions between human APRIL and its receptors can contribute to a better design of APRIL inhibitors.

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► A proliferation-inducing ligand (APRIL) belongs to TNF family and binds TACI and BCMA.
► High levels of mRNA and APRIL have been detected in autoimmune diseases and tumour cells.
► We analyse the interactions between APRIL and its receptors through molecular dynamics to get a better understanding of the interaction between both proteins.
► We build a pharmacophore that can be used to find news inhibitors compounds.
► This is a first step in the modelling of drugs mimicking human_APRIL–TACI/BCMA complexes.