7PAC
The crystal structure of PDE6D in the apo state
Summary for 7PAC
| Entry DOI | 10.2210/pdb7pac/pdb |
| Descriptor | Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta, NICKEL (II) ION, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (4 entities in total) |
| Functional Keywords | inhibitor, complex, protein binding |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 19649.99 |
| Authors | Beaumont, E.,Williams, D. (deposition date: 2021-07-29, release date: 2022-06-08, Last modification date: 2024-01-31) |
| Primary citation | Canovas Nunes, S.,De Vita, S.,Anighoro, A.,Autelitano, F.,Beaumont, E.,Klingbeil, P.,McGuinness, M.,Duvert, B.,Harris, C.,Yang, L.,Pokharel, S.P.,Chen, C.W.,Ermann, M.,Williams, D.A.,Xu, H. Validation of a small molecule inhibitor of PDE6D-RAS interaction with favorable anti-leukemic effects. Blood Cancer J, 12:64-64, 2022 Cited by PubMed Abstract: RAS mutations prevalent in high-risk leukemia have been linked to relapse and chemotherapy resistance. Efforts to directly target RAS proteins have been largely unsuccessful. However, since RAS-mediated transformation is dependent on signaling through the RAS-related C3 botulinum toxin substrate (RAC) small GTPase, we hypothesized that targeting RAC may be an effective therapeutic approach in RAS mutated tumors. Here we describe multiple small molecules capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. One of these, DW0254, also demonstrates promising anti-leukemic activity in RAS-mutated cells. Using chemical proteomics and biophysical methods, we identified the hydrophobic pocket of phosphodiester 6 subunit delta (PDE6D), a known RAS chaperone, as a target for this compound. Inhibition of RAS localization to the plasma membrane upon DW0254 treatment is associated with RAC inhibition through a phosphatidylinositol-3-kinase/AKT-dependent mechanism. Our findings provide new insights into the importance of PDE6D-mediated transport for RAS-dependent RAC activation and leukemic cell survival. PubMed: 35422065DOI: 10.1038/s41408-022-00663-z PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
Download full validation report
