Identification of hot spot residues on serine-arginine protein kinase-1 by molecular dynamics simulation studies

Abstract

Serine-arginine protein kinase-1 (SRPK1) is a highly specific kinase that recognizes serine-arginine dipeptide repeats and phosphorylates SR rich splicing factor ASF/SF2 in a cell-cycle regulated manner. SRPK1 processively phosphorylates serine residues on its substrate ASF/SF2. Elevated expression pattern of both SRPK1 and ASF/SF2 and their association with various carcinomas have established SRPK1 as a potent target for drug design against cancers. In order to develop specific inhibitors the binding of ASF/SF2 to SRPK1 is desired to be selectively interrupted. We have performed molecular dynamics simulation studies on crystal structure of SRPK1 complex with ASF/SF2. The ASF/SF2 acquired a stable binding on the surface of SRPK1 with strong attractive forces. Analysis revealed that there was no major position shifting of the core β-sheet region within the catalytic site of SRPK1 when present in the state of ASF/SF2 bound in comparison to apo form. Global motions of SRPK1 indicated that major stable structural changes occurred after the substrate binding. The interactions between SRPK1 and ASF/SF2 were examined and calculated during molecular dynamics simulation of 1 µs. Molecular dynamics study indicated Arg84, Lys85, Leu86, Lys174, Tyr227 and Leu479 residues of SRPK1 as essential hot spots involved in the stable binding with substrate. Structural analysis of the binding affinity and hot spot investigation provided significant information on ASF/SF2 binding which may also be considered for designing of the novel specific inhibitors of SRPK1 for the applications in cancer therapy. Communicated by Ramaswamy H. Sarma