6g3c

Crystal Structure of JAK2-V617F pseudokinase domain in complex with Compound 2

spinqualitylabelsall models 6g3c, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6g3c is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, EKT Gene: JAK2 (HUMAN) Activity: Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The oncogenic V617F mutation lies in the pseudokinase domain of JAK2, marking it as a potential target for development of compounds that might inhibit the pathogenic activity of the mutant protein. We used differential scanning fluorimetry to identify compounds that bind the JAK2 pseudokinase domain. Crystal structures of five candidate compounds with the wild-type domain reveal their modes of binding. Exploration of analogs of screening hit BI-D1870 led to the identification of compound 2, a 123 nM ligand for the pseudokinase domain. Interestingly, crystal structures of the V617F domain in complex with two unrelated compounds reveal a conformation that is characteristic of the wild-type domain, rather than that previously observed for the V617F mutant. These structures suggest that certain ATP-site ligands can modulate the V617F allosteric site, thereby providing a mechanistic rationale for targeting the pseudokinase domain and a structural foundation for development of more potent and pseudokinase-selective compounds. Discovery and Structural Characterization of ATP-Site Ligands for the Wild-Type and V617F Mutant JAK2 Pseudokinase Domain.,McNally R, Li Q, Li K, Dekker C, Vangrevelinghe E, Jones M, Chene P, Machauer R, Radimerski T, Eck MJ ACS Chem Biol. 2019 Mar 11. doi: 10.1021/acschembio.8b00722. PMID:30763067 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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