TY - JOUR
T1 - Unique MAP Kinase binding sites
AU - Akella, Radha
AU - Moon, Thomas M.
AU - Goldsmith, Elizabeth J.
N1 - Funding Information:
We thank Tianjun Zhou for contributions to this work. This research was supported by NIH grant DK46993 and grant I1128 from the Welch Foundation. Use of the Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Biological and Environmental Research, under Contract No. W-31-109-ENG-38.
PY - 2008/1
Y1 - 2008/1
N2 - 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 p38α has a binding site near its C-terminus discovered in crystallographic studies. Finally, the MAP kinases ERK2 and p38α 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.
AB - 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 p38α has a binding site near its C-terminus discovered in crystallographic studies. Finally, the MAP kinases ERK2 and p38α 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.
KW - FXFP
KW - Inhibitor binding
KW - MAP kinases
KW - PD98059
KW - Sulindac
KW - X-ray crystallography
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U2 - 10.1016/j.bbapap.2007.09.016
DO - 10.1016/j.bbapap.2007.09.016
M3 - Article
C2 - 18068683
AN - SCOPUS:38349000731
SN - 1570-9639
VL - 1784
SP - 48
EP - 55
JO - BBA - Protein Structure
JF - BBA - Protein Structure
IS - 1
ER -