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학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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Extracellular signal-regulated kinase (ERK) is a serine-threonine kinase that is involved in the regulation of cellular signals. ERK inhibitors have been developed to treat cancers with B-Raf proto-oncogene mutations. However, the use of these inhibitors in disease settings induces ERK mutations resistant to the inhibitors, which poses major difficulties in effective cancer treatment. Here, we present the crystal structures of the ERK Y36H and G37C mutants that occur in cancer cells resistant to ERK inhibitors. The structures revealed mechanisms by which these mutations confer inhibitor-resistance to ERK. The Y36H mutant structure revealed a resistance mechanism that involves rotations of the His36 residue in the Gly-rich loop and the Tyr64 residue in the helix C, which blocks the entrance of inhibitors to the ATP-binding pocket. Furthermore, the G37C mutant structure exhibited that the mutation-induced rigidity in dihedral angles plays a major role in inducing inhibitor-resistance. Detailed structural information on the resistance mechanism suggests strategy for designing of novel inhibitors that can circumvent mutation-induced inhibitor resistance.
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참고문헌 (15)
참고문헌 신청
Aronov, A. M. / 2009 / Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase(ERK)using conformational control / J Med Chem 52:6362~6368
Brenan, L. / 2016 / Phenotypic characterization of a comprehensive set of MAPK1/ERK2 missense mutants / Cell Rep 17:1171~1183
Chaikuad, A. / 2014 / A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics / Nat Chem Biol 10:853~860
Emsley, P. / 2010 / Features and development of Coot / Acta Crystallogr D Biol Crystallogr 66:486~501
Garraway, L. A. / 2012 / Circumventing cancer drug resistance in the era of personalized medicine / Cancer Discov 2:214~226
Brenan, L. / 2016 / Phenotypic characterization of a comprehensive set of MAPK1/ERK2 missense mutants / Cell Rep 17:1171~1183
Chaikuad, A. / 2014 / A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics / Nat Chem Biol 10:853~860
Emsley, P. / 2010 / Features and development of Coot / Acta Crystallogr D Biol Crystallogr 66:486~501
Garraway, L. A. / 2012 / Circumventing cancer drug resistance in the era of personalized medicine / Cancer Discov 2:214~226
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