5WIN

JAK2 Pseudokinase in complex with JNJ7706621

Summary for 5WIN

• Entry DOI: 10.2210/pdb5win/pdb
• Descriptor: Tyrosine-protein kinase JAK2, 4-({5-amino-1-[(2,6-difluorophenyl)carbonyl]-1H-1,2,4-triazol-3-yl}amino)benzenesulfonamide (3 entities in total)
• Functional Keywords: jak2, pseudokinase, jnj7706621, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 32075.72

Authors

Li, Q.,Eck, M.J.,Li, K.,Park, E. (deposition date: 2017-07-19, release date: 2018-08-01, Last modification date: 2024-03-13)

Primary citation

McNally, R.,Li, Q.,Li, K.,Dekker, C.,Vangrevelinghe, E.,Jones, M.,Chene, P.,Machauer, R.,Radimerski, T.,Eck, M.J.
Discovery and Structural Characterization of ATP-Site Ligands for the Wild-Type and V617F Mutant JAK2 Pseudokinase Domain.
ACS Chem. Biol., 14:587-593, 2019

PubMed Abstract: 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.

PubMed: 30763067
DOI: 10.1021/acschembio.8b00722

Experimental method

X-RAY DIFFRACTION (2.38 Å)