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ATP Site Ligands Determine the Assembly State of the Abelson Kinase Regulatory Core via the Activation Loop Conformation

Sonti, Rajesh and Hertel-Hering, Ines and Lamontanara, Allan Joaquim and Hantschel, Oliver and Grzesiek, Stephan. (2018) ATP Site Ligands Determine the Assembly State of the Abelson Kinase Regulatory Core via the Activation Loop Conformation. Journal of the American Chemical Society, 140 (5). pp. 1863-1869.

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Official URL: https://edoc.unibas.ch/67050/

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Abstract

The constituent SH3, SH2, and kinase domains of the Abl kinase regulatory core can adopt an assembled (inactive) or a disassembled (active) conformation. We show that this assembly state strictly correlates with the conformation of the kinase activation loop induced by a total of 14 ATP site ligands, comprising all FDA-approved Bcr-Abl inhibiting drugs. The disassembly of the core by certain (type II) ligands can be explained by an induced push on the kinase N-lobe via A- and P-loop toward the SH3 domain. A similar sized P-loop motion is expected during nucleotide binding and release, which would be impeded in the assembled state, in agreement with its strongly reduced kinase activity.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Grzesiek)
UniBasel Contributors:Grzesiek, Stephan and Sonti, Rajesh and Hertel-Hering, Ines
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
ISSN:1520-5126
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Language:English
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Last Modified:21 Dec 2018 13:45
Deposited On:21 Dec 2018 13:40

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