8fe9

Crystal structure of Ack1 kinase K161Q mutant in complex with the selective inhibitor (R)-9b

spinqualitylabelsall models 8fe9, resolution 3.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8fe9 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.2Å Ligands: WTP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Tyrosine kinases (TKs) play essential roles in signaling processes that regulate cell survival, migration, and proliferation. Dysregulation of tyrosine kinases underlies many disorders, including cancer, cardiovascular and developmental diseases, as well as pathologies of the immune system. Ack1 and Brk are nonreceptor tyrosine kinases (NRTKs) best known for their roles in cancer. Here, we have biochemically characterized novel Ack1 and Brk mutations identified in patients with systemic lupus erythematosus (SLE). These mutations are the first SLE-linked polymorphisms found among NRTKs. We show that two of the mutants are catalytically inactive, while the other three have reduced activity. To understand the structural changes associated with the loss-of-function phenotype, we solved the crystal structure of one of the Ack1 kinase mutants, K161Q. Furthermore, two of the mutated residues (Ack1 A156 and K161) critical for catalytic activity are highly conserved among other TKs, and their substitution in other members of the kinase family could have implications in cancer. In contrast to canonical gain-of-function mutations in TKs observed in many cancers, we report loss-of-function mutations in Ack1 and Brk, highlighting the complexity of TK involvement in human diseases. Biochemical Studies of Systemic Lupus Erythematosus-Associated Mutations in Nonreceptor Tyrosine Kinases Ack1 and Brk.,Kan Y, Paung Y, Kim Y, Seeliger MA, Miller WT Biochemistry. 2023 Mar 21;62(6):1124-1137. doi: 10.1021/acs.biochem.2c00685. Epub , 2023 Feb 28. PMID:36854171 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tyrosine kinase 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA