9RP7
Crystal structure of covalent PDE6delta adduct modified by Deltafluorine (22a)
This is a non-PDB format compatible entry.
Summary for 9RP7
| Entry DOI | 10.2210/pdb9rp7/pdb |
| Descriptor | Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta, ~{N}1-[(4-chlorophenyl)methyl]-~{N}1-cyclopentyl-~{N}4-[[5-(fluoranylmethyl)-2,6-dimethyl-pyridin-3-yl]methyl]-~{N}4-(piperidin-4-ylmethyl)benzene-1,4-disulfonamide (3 entities in total) |
| Functional Keywords | pde6delta, glutamic acid labelling, targetted covalent inhibitor, chaperone |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 18947.17 |
| Authors | |
| Primary citation | Zhang, R.,Huetzen, M.A.,Binici, A.,Martin-Gago, P.,Gasper, R.,Rudashevskaya, E.,Liu, J.,Nagaraju, C.,Reckzeh, E.S.,Stuedle, A.S.T.,Hopff, A.S.,Mesaros, A.,Unger, A.,Thelen, M.,Janning, P.,Reinhardt, H.C.,Ziegler, S.,Jachimowicz, R.D.,Waldmann, H. Targeting a Glutamic Acid in PDE delta with Fluoromethyl-Aryl Electrophiles Impairs K-Ras Signaling. J.Med.Chem., 69:964-981, 2026 Cited by PubMed Abstract: 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 PDEδ, 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-driven lung adenocarcinoma, Deltafluorine treatment significantly reduces tumor volume. PubMed: 41499451DOI: 10.1021/acs.jmedchem.5c02082 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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