9ZB9
Cryo-EM Structure of Human GGPPS Bound to Selective Inhibitor CML-07-119
This is a non-PDB format compatible entry.
Summary for 9ZB9
| Entry DOI | 10.2210/pdb9zb9/pdb |
| Related | 9ZB8 |
| EMDB information | 73979 |
| Descriptor | Geranylgeranyl pyrophosphate synthase, {[(2-{3-[(3-fluoro-4-methoxyphenyl)carbamoyl]phenyl}thieno[2,3-d]pyrimidin-4-yl)amino]methylene}bis(phosphonic acid), MAGNESIUM ION, ... (4 entities in total) |
| Functional Keywords | inhibitor, complex, isoprenoid, synthesis, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 6 |
| Total formula weight | 213685.24 |
| Authors | Ferens, F.G.,Tsantrizos, Y.S.,Lemieux, M.J. (deposition date: 2025-11-20, release date: 2026-09-09, Last modification date: 2026-11-04) |
| Primary citation | Ferens, F.G.,Waller, D.D.,Boutin, R.,Lee, H.F.,Tremblay, M.,Saba-El-Leil, M.K.,Guan, T.L.,Skorey, K.,Grignano, E.,Sebag, M.,Wiita, A.P.,Lemieux, M.J.,Tsantrizos, Y.S. Structural and Functional Analysis of GGPPS Inhibition as a Therapeutic Mechanism for Acute Myeloid Leukemia. J.Med.Chem., 69:21862-21878, 2026 Cited by PubMed Abstract: Acute myeloid leukemia (AML) is a hematological malignancy with poor treatment options and high mortality rates. AML progression is influenced by signaling events facilitated by small GTPases anchored to cellular membranes via post-translational modification with geranylgeranyl pyrophosphate (GGPP). Herein, we show that CML-07-119, a selective inhibitor of GGPP synthase (GGPPS), exhibits nanomolar potency in blocking the viability of AML cell lines, including cells with TP53 wild-type and TP53 mutations, and has antitumor efficacy in vivo. Bone marrow and splenocytes harvested from mice treated with CML-07-119 displayed significantly higher concentrations of unprenylated RAP1A as compared to the controls, confirming the expected biochemical outcome of in vivo GGPPS inhibition. X-ray crystallography and cryo-EM were used to determine the binding mode of this compound and to identify conformational changes to the GGPPS quaternary structure upon binding of CML-07-119. These studies strongly support GGPPS inhibition as a novel mechanism for the treatment of AML. PubMed: 42917932DOI: 10.1021/acs.jmedchem.6c00808 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (1.95 Å) |
Structure validation
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