9B4P
Tetramer Formation of the BCL11A ZF0 Domain
Summary for 9B4P
| Entry DOI | 10.2210/pdb9b4p/pdb |
| Descriptor | B-cell lymphoma/leukemia 11A, ZINC ION (3 entities in total) |
| Functional Keywords | sickle cell disease, bcl11a, tetramerization, hemoglobin, transcription factor, transcription |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 10 |
| Total formula weight | 33062.92 |
| Authors | |
| Primary citation | Zheng, G.,Yin, M.,Mehta, S.,Chu, I.T.,Wang, S.,AlShaye, A.,Drainville, K.,Buyanbat, A.,Bienfait, F.,Tenglin, K.,Zhu, Q.,Orkin, S.H. A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing. Science, 386:1010-1018, 2024 Cited by PubMed Abstract: Down-regulation of BCL11A protein reverses the fetal (HbF, αγ) to adult (HbA, αβ) hemoglobin switch and is exploited in gene-based therapy for hemoglobin disorders. Because of reliance on ex vivo cell manipulation and marrow transplant, such therapies cannot lessen disease burden. To develop new small-molecule approaches, we investigated the state of BCL11A protein in erythroid cells. We report that tetramer formation mediated by a single zinc finger (ZnF0) is required for production of steady-state protein. Beyond its role in protein stability, the tetramer state is necessary for γ-globin gene repression, because an engineered monomer fails to engage a critical co-repressor complex. These aspects of BCL11A protein production identify tetramer formation as a vulnerability for HbF silencing and provide opportunities for drug discovery. PubMed: 39607926DOI: 10.1126/science.adp3025 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.56 Å) |
Structure validation
Download full validation report
