Reviving B-Factors: Activating ALK Mutations Increase Protein Dynamics of the Unphosphorylated Kinase
| Autor: | Dan Gehlhaar, Alexei Brooun, Mehran Jalaie, Michele McTigue, Sergei Timofeevski, Ben Bolaños, Gallego Rebecca Anne, Ted William Johnson |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Mutation biology Chemistry Kinase Organic Chemistry Mutant Wild type medicine.disease_cause Biochemistry Receptor tyrosine kinase Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Protein kinase domain 030220 oncology & carcinogenesis hemic and lymphatic diseases Drug Discovery biology.protein medicine Anaplastic lymphoma kinase Phosphorylation |
| Zdroj: | ACS medicinal chemistry letters. 9(9) |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that can become oncogenic by activating mutations or overexpression. Full kinetic characterization of both phosphorylated and nonphosphorylated wildtype and mutant ALK kinase domain was done. Our structure-based drug design programs directed at ALK allowed us to interrogate whether X-ray crystallography data could be used to support the hypothesis that activation of ALK by mutation occurs due to increased protein dynamics. Crystallographic B-factors were converted to normalized B-factors, which allowed analysis of wildtype ALK, ALK-C1156Y, and ALK-L1196M. This data suggests that mobility of the P-loop, αC-helix, and activation loop (A-loop) may be important in catalytic activity increases, with or without phosphorylation. Both molecular dynamics simulations and hydrogen–deuterium exchange experimental data corroborated the normalized B-factors data. |
| Databáze: | OpenAIRE |
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