8tjl | pdb_00008tjl

EGFR kinase in complex with pyrazolopyrimidine covalent inhibitor

spinqualitylabelsall models 8tjl, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8tjl 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 2.7Å Ligands: HZ6 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The pyrazolopyrimidine (PP) heterocycle is a versatile and widely deployed core scaffold for the development of kinase inhibitors. Typically, a 4-amino-substituted pyrazolopyrimidine binds in the ATP-binding pocket in a conformation analogous to the 6-aminopurine of ATP. Here, we report the discovery of ZNL0325 which exhibits a flipped binding mode where the C3 position is oriented toward the ribose binding pocket. ZNL0325 and its analogues feature an acrylamide side chain at the C3 position which is capable of forming a covalent bond with multiple kinases that possess a cysteine at the alphaD-1 position including BTK, EGFR, BLK, and JAK3. These findings suggest that the ability to form a covalent bond can override the preferred noncovalent binding conformation of the heterocyclic core and provides an opportunity to create structurally distinct covalent kinase inhibitors. ZNL0325, a Pyrazolopyrimidine-Based Covalent Probe, Demonstrates an Alternative Binding Mode for Kinases.,Li Z, Lu W, Beyett TS, Ficarro SB, Jiang J, Tse J, Kim AY, Marto JA, Che J, Janne PA, Eck MJ, Zhang T, Gray NS J Med Chem. 2024 Feb 22;67(4):2837-2848. doi: 10.1021/acs.jmedchem.3c01891. Epub , 2024 Feb 1. PMID:38300264 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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