PIM1 + Pimtide

PIM1 + Pimtide

PIM1 + Pimtide: Human Proviral Integration Site for MulV in complex with consensus peptide and BIM-1
PDB Code: 2BIL
Description
Pim1 phosphorylates a number of signal transduction proteins like the transcription factor cMyb, the suppressor of cytokine signaling SOCS, pro-apoptotic protein Bad, phosphatase cdc25, HSP90, the kinase c-TAK as well as proteins necessary for mitosis and thereby modulates signal transduction pathways involved in the regulation of cell cycle, apoptosis, differentiation and proliferation. Comparison of phosphorylation sites showed that the Pim recognition sequences need to contain basic residues at positions -3 and -5. Combinatorial peptide library methods showed also a strong preference for histidine at position -2, proline at -1 as well as glycine at position +1.
We determined the crystal structure of Pim1 in complex with the consensus peptide ARKRRRHPS*GPPTA (consensus peptide; pimtide) which binds to Pim1 with a dissociation constant of 18 nM (Figure 1). Electron density was clearly visible for the substrate residues Arg -5 to the substrate serine Ser 0. As expected the crystal structure showed that ser 0 is in close proximity to the catalytic base Asp167 (3 Å). Pro in position -1 exposes its side chain to the solvent and serves probably to constrain the orientation of the peptide. His -2 packs nicely into a pocked formed by the C terminal section of the activation loop as well as the catalytic loop and forms a hydrogen bond with the Pim1 residue Glu243. Most strikingly the peptide residue Arg-3 forms a large number of salt bridges with an acidic cluster formed by the Pim1 residues Asp131, Asp127 and Glu171 as well as a hydrophobic interaction with Phe130. In addition, this peptide side chain is in close proximity with the aliphatic tertiary amine moiety of BIM1 (3.4 Å) which would potentially allow linking of the substrate peptide with this ATP mimetic inhibitor to create a more potent and specific inhibitor. The substrate residue Arg -4 is quite solvent exposed and forms only one hydrogen bond with Glu243. Arg-5 binds to another very acidic pocked adjacent to the binding pocket of Arg-3. The two binding pockets are separated by Phe130. Apart from the interaction with Phe130 the substrate residue Arg-5 forms multiple polar interactions with the Pim1 residues Asp170, Asp239, Asp234 and Thr134.

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