6OCC

JAK2 JH2 in complex with JAK190

Summary for 6OCC

• Entry DOI: 10.2210/pdb6occ/pdb
• Descriptor: Tyrosine-protein kinase JAK2, GLYCEROL, 2-[4-({5-amino-3-[(4-sulfamoylphenyl)amino]-1H-1,2,4-triazole-1-carbonyl}amino)phenyl]-1,3-oxazole-4-carboxylic acid, ... (4 entities in total)
• Functional Keywords: pseudokinase domain, inhibitor, complex, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33697.50

Authors

Krimmer, S.G.,Liosi, M.E.,Schlessinger, J.,Jorgensen, W.L. (deposition date: 2019-03-22, release date: 2020-03-25, Last modification date: 2023-10-11)

Primary citation

Liosi, M.E.,Krimmer, S.G.,Newton, A.S.,Dawson, T.K.,Puleo, D.E.,Cutrona, K.J.,Suzuki, Y.,Schlessinger, J.,Jorgensen, W.L.
Selective Janus Kinase 2 (JAK2) Pseudokinase Ligands with a Diaminotriazole Core.
J.Med.Chem., 63:5324-5340, 2020

PubMed Abstract: Janus kinases (JAKs) are non-receptor tyrosine kinases that are essential components of the JAK-STAT signaling pathway. Associated aberrant signaling is responsible for many forms of cancer and disorders of the immune system. The present focus is on the discovery of molecules that may regulate the activity of JAK2 by selective binding to the JAK2 pseudokinase domain, JH2. Specifically, the Val617Phe mutation in JH2 stimulates the activity of the adjacent kinase domain (JH1) resulting in myeloproliferative disorders. Starting from a non-selective screening hit, we have achieved the goal of discovering molecules that preferentially bind to the ATP binding site in JH2 instead of JH1. We report the design and synthesis of the compounds and binding results for the JH1, JH2, and JH2 V617F domains, as well as five crystal structures for JH2 complexes. Testing with a selective and non-selective JH2 binder on the autophosphorylation of wild-type and V617F JAK2 is also contrasted.

PubMed: 32329617
DOI: 10.1021/acs.jmedchem.0c00192

Experimental method

X-RAY DIFFRACTION (2.03 Å)