8JUE
Crystal structure of glutaminase C in complex with compound 11
Summary for 8JUE
| Entry DOI | 10.2210/pdb8jue/pdb |
| Descriptor | Glutaminase kidney isoform, mitochondrial, 2-(3-phenoxyphenyl)-N-[5-[[(3R)-1-pyridazin-3-ylpyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]ethanamide (3 entities in total) |
| Functional Keywords | inhibitor, complex, antitumor protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 236070.54 |
| Authors | Wang, X.,Hanyu, S.,Tingting, D. (deposition date: 2023-06-26, release date: 2023-10-11, Last modification date: 2023-11-01) |
| Primary citation | Sun, H.,Du, T.,Yang, M.,Liu, X.,Xue, X.,Chen, K.,Lang, X.,Chen, X.,Wang, B.,Wang, X. Targeting the Subpocket Enables the Discovery of Thiadiazole-Pyridazine Derivatives as Glutaminase C Inhibitors. Acs Med.Chem.Lett., 14:1455-1466, 2023 Cited by PubMed Abstract: As glutaminase C (GAC) has become an attractive target for cancer treatment by regulating glutaminolysis, thus, interest in GAC inhibitors has risen in recent years. Herein, a potential binding subpocket comprising basic residues was identified, and through extensive structure-activity relationship studies, promising inhibitors and were identified with robust GAC inhibitory activity and A549 cell antiproliferative activity. X-ray crystallography of the -GAC and -GAC complexes revealed a novel binding mode against GAC. The potency of and against GAC further highlighted the importance of the binding. Notably, compounds and regulated the cellular metabolite, thereby increasing reactive oxygen species by blocking glutamine metabolism. Compound also exhibited excellent antiproliferative activity in the A549 cell xenograft model. We further proved that is a safe GAC allosteric inhibitor. A basic subpocket is proposed that might provide new strategies for the development of novel GAC inhibitors in the future. PubMed: 37849538DOI: 10.1021/acsmedchemlett.3c00375 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.39 Å) |
Structure validation
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