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Sequence determinants of a specific inactive protein kinase conformation.

Hari SB, Merritt EA, Maly DJ
Chem Biol 20 806-15 (2013)
Cited: 47 times
EuropePMC logo PMID: 23790491

Abstract

Only a small percentage of protein kinases have been shown to adopt a distinct inactive ATP-binding site conformation, called the Asp-Phe-Gly-out (DFG-out) conformation. Given the high degree of homology within this enzyme family, we sought to understand the basis of this disparity on a sequence level. We identified two residue positions that sensitize mitogen-activated protein kinases (MAPKs) to inhibitors that stabilize the DFG-out inactive conformation. After characterizing the structure and dynamics of an inhibitor-sensitive MAPK mutant, we demonstrated the generality of this strategy by sensitizing a kinase (apoptosis signal-regulating kinase 1) not in the MAPK family to several DFG-out stabilizing ligands, using the same residue positions. The use of specific inactive conformations may aid the study of noncatalytic roles of protein kinases, such as binding partner interactions and scaffolding effects.

Articles - 4i5h mentioned but not cited (2)

  1. Sequence determinants of a specific inactive protein kinase conformation. Hari SB, Merritt EA, Maly DJ. Chem Biol 20 806-815 (2013)
  2. Conformation-selective ATP-competitive inhibitors control regulatory interactions and noncatalytic functions of mitogen-activated protein kinases. Hari SB, Merritt EA, Maly DJ. Chem Biol 21 628-635 (2014)


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