9rp7

Crystal structure of covalent PDE6delta adduct modified by Deltafluorine (22a)

spinqualitylabelsall models 9rp7, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9rp7 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 1.9Å Ligands: A1JIB Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PDE6D_HUMAN Acts as a GTP specific dissociation inhibitor (GDI). Increases the affinity of ARL3 for GTP by several orders of magnitude and does so by decreasing the nucleotide dissociation rate. Stabilizes Arl3-GTP by decreasing the nucleotide dissociation (By similarity). Publication Abstract from PubMed For targeted covalent modification at low-reactivity carboxylates with biocompatible electrophiles, new approaches are in high demand. Engineering of the HaloTag protein facilitates such a covalent reaction between chloroalkanes and an aspartate residue. We demonstrate that conversely, engineering stable ligands can also enable covalent targeting of an acid residue in a protein binding site. Using the chaperone PDEdelta, which shuttles lipidated oncoproteins and thereby mediates their signaling activity, we show that equipping noncovalent inhibitors with a benzyl fluoride-based electrophile leads to covalent modification of a specific glutamate p.E88 in the ligand binding site. The best inhibitor, Deltafluorine, embodies a 3-fluoromethyl-pyridyl group and is stable to nucleophiles like glutathione, phosphate, acetate, and citrate. In cells, Deltafluorine combines noncovalent and covalent reactivity to demonstrate distinct cellular profiles and inhibits signaling through the MAP-kinase and Akt-mTOR pathways. In an autochthonous mouse model of highly aggressive Kras(G12D)-driven lung adenocarcinoma, Deltafluorine treatment significantly reduces tumor volume. Targeting a Glutamic Acid in PDEdelta with Fluoromethyl-Aryl Electrophiles Impairs K-Ras Signaling.,Zhang R, Huetzen MA, Binici A, Martin-Gago P, Gasper R, Rudashevskaya E, Liu J, Nagaraju C, Reckzeh ES, Stuedle AST, Hopff AS, Mesaros A, Unger A, Thelen M, Janning P, Reinhardt HC, Ziegler S, Jachimowicz RD, Waldmann H J Med Chem. 2026 Jan 22;69(2):964-981. doi: 10.1021/acs.jmedchem.5c02082. Epub , 2026 Jan 7. PMID:41499451 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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