9hhw

Crystal structure of TTBK1 with a covalent compound GCL95

spinqualitylabelsall models 9hhw, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9hhw 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 3Å Ligands: A1IU7 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TTBK1_HUMAN Serine/threonine kinase which is able to phosphorylate TAU on serine, threonine and tyrosine residues. Induces aggregation of TAU. Publication Abstract from PubMed Protein kinases are important drug targets, yet specific inhibitors have been developed for only a fraction of the more than 500 human kinases. A major challenge in designing inhibitors for highly related kinases is selectivity. Unlike their non-covalent counterparts, covalent inhibitors offer the advantage of selectively targeting structurally similar kinases by modifying specific protein side chains, particularly non-conserved cysteines. Previously, covalent fragment screens yielded potent and selective compounds for individual kinases such as ERK1/2 but have not been applied to the broader kinome. Furthermore, many of the accessible cysteine positions have not been addressed so far. Here, we outline a generalizable approach to sample ATP-site cysteines with fragment-like covalent inhibitors. We present the development of a kinase-focused fragment library and its systematic screening against a curated selection of 47 kinases, with 60 active site-proximal cysteines using LC/MS and differential scanning fluorimetry (DSF) assays, followed by hit validation through various complementary techniques. Our findings expand the repertoire of targetable cysteines within protein kinases, provide insight into unique binding modes identified from crystal structures and deliver isoform-specific hits with promising profiles as starting points for the development of highly potent and selective covalent inhibitors. Probing the Protein Kinases' Cysteinome by Covalent Fragments.,Wang G, Seidler NJ, Rohm S, Pan Y, Liang XJ, Haarer L, Berger BT, Sivashanmugam SA, Wydra VR, Forster M, Laufer SA, Chaikuad A, Gehringer M, Knapp S Angew Chem Int Ed Engl. 2024 Dec 24:e202419736. doi: 10.1002/anie.202419736. PMID:39716901 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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