9HMD
Crystal structure of PDE6D in complex with DeltaTag (6a)
This is a non-PDB format compatible entry.
Summary for 9HMD
| Entry DOI | 10.2210/pdb9hmd/pdb |
| Descriptor | Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta, 4-[3,4-dimethyl-2-(4-methylphenyl)-7-oxidanylidene-pyrazolo[3,4-d]pyridazin-6-yl]-~{N}-[2-(3-ethylphenyl)ethyl]-~{N}-(piperidin-4-ylmethyl)butane-1-sulfonamide (3 entities in total) |
| Functional Keywords | pde6d, bromoalkane warheads, glutamic acid labelling, targetted covalent inhibitor, lipid binding protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 37777.42 |
| Authors | Zhang, R.,Waldmann, H.,Gasper, R. (deposition date: 2024-12-09, release date: 2025-12-24, Last modification date: 2026-07-08) |
| Primary citation | Zhang, R.,Liu, J.,Gasper, R.,Unger, A.,Kaschani, F.,Kaiser, M.,Janning, P.,Waldmann, H. Covalent modification of a glutamic acid inspired by HaloTag technology. Nat Commun, 17:1257-1257, 2026 Cited by PubMed Abstract: For targeted covalent protein modification at low-reactivity aspartates and glutamates, new methods are in high demand. We report a technique inspired by the HaloTag technology, which employs nucleophilic substitution at chloroalkane-functionalised ligands by a specific aspartate residue. Embedding of alkyl bromide warheads into non-covalent inhibitors enables covalent modification of a glutamate in the lipoprotein binding chaperone - phosphodiesterase of retinal rod subunit delta (PDEδ), which shuttles prenylated lipoproteins between cellular membranes and thereby mediates their activity. Its hydrophobic ligand-binding pocket contains p.E88 as the only accessible nucleophile for covalent targeting. We show that a covalent inhibitor, termed DeltaTag, overcomes limitations of non-covalent inhibitors. DeltaTag labels PDEδ at its p.E88 under biologically relevant conditions, modulates mammalian target of rapamycin (mTOR) signalling by disrupting the PDEδ-Rheb (Ras homologue enriched in brain)-mTORC1 (mTOR complex 1) axis and inhibits cancer cell proliferation. This proof-of-concept study demonstrates that the design strategy holds promise for the covalent modification of proteins with lipophilic binding sites that lack accessible reactive amino acids but contain specific carboxylates. PubMed: 41617704DOI: 10.1038/s41467-026-68999-9 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
Download full validation report
