Unique MAP Kinase binding sites

Abstract

Map kinases are drug targets for autoimmune disease, cancer, and apoptosis-related diseases. Drug discovery efforts have developed MAP kinase inhibitors directed toward the ATP binding site and neighboring "DFG-out" site, both of which are targets for inhibitors of other protein kinases. On the other hand, MAP kinases have unique substrate and small molecule binding sites that could serve as inhibition sites. The substrate and processing enzyme D-motif binding site is present in all MAP kinases, and has many features of a good small molecule binding site. Further, the MAP kinase p38alpha has a binding site near its C-terminus discovered in crystallographic studies. Finally, the MAP kinases ERK2 and p38alpha have a second substrate binding site, the FXFP binding site that is exposed in active ERK2 and the D-motif peptide induced conformation of MAP kinases. Crystallographic evidence of these latter two binding sites is presented.

Mechanism of Mpk1 Mitogen-Activated Protein Kinase Binding to the Swi4 Transcription Factor and Its Regulation by a Novel Caffeine-Induced Phosphorylation

“…Transformants were grown as described above and diluted into 100 ml of medium so that subsequent incubation at 23°C, 39°C, or 23°C with 8 mM caffeine (MPK1 only) for 15 h resulted in mid-log-phase cultures (A 600 of 1.0 to 1. (Arg/Lys) 1-2 -X 2-6 -⌽ A -x-⌽ B (where ⌽ indicates hydrophobic residues Leu, Ile, and Val) (2,39,42,59). The basic residues interact with an acidic patch within the MAPK DB site called the common docking site (59), and the hydrophobic residues bind to a hydrophobic groove that is adjacent to the common docking site (11,19).…”

“…MAPKs bind to their substrates and regulators through two distinct protein-protein interaction sites. A docking sequence (D motif) on the substrate or regulator engages in a highaffinity interaction with the D-motif-binding (DB) site of the MAPK, which is remote from the active site and is comprised of an acidic patch called the common docking site and a hydrophobic docking groove (2,59). The bound protein wraps around the MAPK to make additional contacts with a second surface called the substrate-binding (SB) site, which is positioned near the catalytic center (59).…”

Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts

“…Unlike KA-BAS, KR-BAS was able to bind to ERK2 and inhibit osteoblast differentiation, consistent with the model that these 3 lysines function by regulating the interaction of SHN3 with ERK2. The common docking domain (CD-domain) of MAPKs mediates the interactions with the D-domain of MAPK substrates (22,24,25). To examine whether the D-domain of SHN3 interacts with the CD-domain of ERK2, in vitro interaction analysis using an ERK2 containing a CD-domain mutation (p.[D319N]) was performed ( Figure 3C and refs.…”

Perspective on the Discovery and Scientific Impact of p38 MAP Kinase

“…42,43 Another feature contributing to the specificity of p38 inhibition of SB203580 was highlighted by the discovery of three closely related homologues, p38β, γ, and δ. SB203580 inhibits the original p38/CSBP, now named p38α, and p38β but not the γ or δ homologues. 44 The γ and δ kinases differ from α and β in the absence of a small amino acid (Thr106) in the loop at the back of the ATP and SB203580 binding pocket, which is replaced by a methionine.…”