6CDT

Structure of Human Anaplastic Lymphoma Kinase Domain

Summary for 6CDT

• Entry DOI: 10.2210/pdb6cdt/pdb
• Descriptor: ALK tyrosine kinase receptor (2 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 36909.36

Authors

McTigue, M.,Deng, Y.L.,Liu, W.,Brooun, A. (deposition date: 2018-02-09, release date: 2019-02-20, Last modification date: 2023-10-04)

Primary citation

Johnson, T.W.,Bolanos, B.,Brooun, A.,Gallego, R.A.,Gehlhaar, D.,Jalaie, M.,McTigue, M.,Timofeevski, S.
Reviving B-Factors: Activating ALK Mutations Increase Protein Dynamics of the Unphosphorylated Kinase.
ACS Med Chem Lett, 9:872-877, 2018

PubMed Abstract: 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.

PubMed: 30258533
DOI: 10.1021/acsmedchemlett.8b00348

Experimental method

X-RAY DIFFRACTION (1.8 Å)