6PGU
Crystal structure of the p300 acetyltransferase domain with allosteric inhibitor CPI-076 and CoA
Summary for 6PGU
| Entry DOI | 10.2210/pdb6pgu/pdb |
| Descriptor | Histone acetyltransferase p300, COENZYME A, N-(thiophen-2-yl)acetamide, ... (4 entities in total) |
| Functional Keywords | ep300, p300 acetyltransferase, chromatin modification, epigenetics, inhibitor, allosteric, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 76188.41 |
| Authors | Gardberg, A.S.,Poy, F.,Setser, J. (deposition date: 2019-06-24, release date: 2019-10-23, Last modification date: 2024-05-22) |
| Primary citation | Gardberg, A.S.,Huhn, A.J.,Cummings, R.,Bommi-Reddy, A.,Poy, F.,Setser, J.,Vivat, V.,Brucelle, F.,Wilson, J. Make the right measurement: Discovery of an allosteric inhibition site for p300-HAT. Struct Dyn., 6:054702-054702, 2019 Cited by PubMed Abstract: Histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the dynamic and reversible acetylation of proteins, an epigenetic regulatory mechanism associated with multiple cancers. Indeed, HDAC inhibitors are already approved in the clinic. The HAT paralogs p300 and CREB-binding protein (CBP) have been implicated in human pathological conditions including several hematological malignancies and androgen receptor-positive prostate cancer. Others have reported CoA-competitive inhibitors of p300 and CBP with cell-based activity. Here, we describe 2 compounds, CPI-076 and CPI-090, discovered through p300-HAT high throughput screening screening, which inhibit p300-HAT via binding at an allosteric site. We present the high resolution (1.7 and 2.3 Å) co-crystal structures of these molecules bound to a previously undescribed allosteric site of p300-HAT. Derivatization yielded actionable structure-activity relationships, but the full-length enzymatic assay demonstrated that this allosteric HAT inhibitor series was artifactual, inhibiting only the HAT domain of p300 with no effect on the full-length enzyme. PubMed: 31649965DOI: 10.1063/1.5119336 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.72 Å) |
Structure validation
Download full validation report
