4I5H

Crystal Structure of a Double Mutant Rat Erk2 Complexed With a Type II Quinazoline Inhibitor

Summary for 4I5H

• Entry DOI: 10.2210/pdb4i5h/pdb
• Descriptor: Mitogen-activated protein kinase 1, N-{3-[2-(cyclopropylamino)quinazolin-6-yl]-4-methylphenyl}-3-(trifluoromethyl)benzamide (3 entities in total)
• Functional Keywords: map kinase, dfg-out, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Rattus norvegicus (brown rat,rat,rats)
• Cellular location: Cytoplasm, cytoskeleton, spindle (By similarity): P63086
• Total number of polymer chains: 1
• Total formula weight: 41815.97

Authors

Hari, S.B.,Maly, D.J.,Merritt, E.A. (deposition date: 2012-11-28, release date: 2013-07-10, Last modification date: 2024-02-28)

Primary citation

Hari, S.B.,Merritt, E.A.,Maly, D.J.
Sequence determinants of a specific inactive protein kinase conformation.
Chem.Biol., 20:806-815, 2013

PubMed 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.

PubMed: 23790491
DOI: 10.1016/j.chembiol.2013.05.005

Experimental method

X-RAY DIFFRACTION (1.9 Å)