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Pathological role of a point mutation (T315I) in BCR-ABL1 protein-A computational insight.
Rajendran, Vidya; Gopalakrishnan, Chandrasekhar; Sethumadhavan, Rao.
Afiliação
  • Rajendran V; Computational Biology Lab, Department of Biotechnology, Vellore Institute of Technology University, Vellore, Tamil Nadu, India.
  • Gopalakrishnan C; Department of biochemistry and molecular biology, Cumming School of Medicine, University of Calgary, Calgary, Canada.
  • Sethumadhavan R; Computational Biology Lab, Department of Biotechnology, Vellore Institute of Technology University, Vellore, Tamil Nadu, India.
J Cell Biochem ; 119(1): 918-925, 2018 01.
Article em En | MEDLINE | ID: mdl-28681927
BCR-ABL protein is one of the most potent target to treat chronic myeloid leukemia (CML). Apart from other mutations, T315I is especially challenging as it confers resistance to all first- and second-generation tyrosine kinase inhibitors. So, a thorough study of altered behavior upon mutation is crucially needed. To understand the resistance mechanism of mutant BCR-ABL protein, we organized a long-term molecular dynamics simulation (500 ns) and performed the detailed comparative conformational analysis. We found that due to mutation at 315th position (threonine to isoleucine), original structures deviated from normal, and attained a flexible conformation. Our observations pave a clear path toward designing new inhibitors against resistant BCR-ABL1 protein and suggest a strategy where additional flexibility governed by mutation could be given an appropriate consideration.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Fusão bcr-abl / Mutação Puntual / Resistencia a Medicamentos Antineoplásicos / Biologia Computacional Limite: Humans Idioma: En Revista: J Cell Biochem Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Índia

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Fusão bcr-abl / Mutação Puntual / Resistencia a Medicamentos Antineoplásicos / Biologia Computacional Limite: Humans Idioma: En Revista: J Cell Biochem Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Índia