7EOD
MITF HLHLZ Delta AKE
Summary for 7EOD
Entry DOI | 10.2210/pdb7eod/pdb |
Descriptor | Isoform M1 of Microphthalmia-associated transcription factor, GLYCEROL (3 entities in total) |
Functional Keywords | transcription factor, transcription |
Biological source | Homo sapiens (Human) |
Total number of polymer chains | 4 |
Total formula weight | 35961.43 |
Authors | |
Primary citation | Liu, Z.,Chen, K.,Dai, J.,Xu, P.,Sun, W.,Liu, W.,Zhao, Z.,Bennett, S.P.,Li, P.,Ma, T.,Lin, Y.,Kawakami, A.,Yu, J.,Wang, F.,Wang, C.,Li, M.,Chase, P.,Hodder, P.,Spicer, T.P.,Scampavia, L.,Cao, C.,Pan, L.,Dong, J.,Chen, Y.,Yu, B.,Guo, M.,Fang, P.,Fisher, D.E.,Wang, J. A unique hyperdynamic dimer interface permits small molecule perturbation of the melanoma oncoprotein MITF for melanoma therapy. Cell Res., 33:55-70, 2023 Cited by PubMed Abstract: Microphthalmia transcription factor (MITF) regulates melanocyte development and is the "lineage-specific survival" oncogene of melanoma. MITF is essential for melanoma initiation, progression, and relapse and has been considered an important therapeutic target; however, direct inhibition of MITF through small molecules is considered impossible, due to the absence of a ligand-binding pocket for drug design. Here, our structural analyses show that the structure of MITF is hyperdynamic because of its out-of-register leucine zipper with a 3-residue insertion. The dynamic MITF is highly vulnerable to dimer-disrupting mutations, as we observed that MITF loss-of-function mutations in human Waardenburg syndrome type 2 A are frequently located on the dimer interface and disrupt the dimer forming ability accordingly. These observations suggest a unique opportunity to inhibit MITF with small molecules capable of disrupting the MITF dimer. From a high throughput screening against 654,650 compounds, we discovered compound TT-012, which specifically binds to dynamic MITF and destroys the latter's dimer formation and DNA-binding ability. Using chromatin immunoprecipitation assay and RNA sequencing, we showed that TT-012 inhibits the transcriptional activity of MITF in B16F10 melanoma cells. In addition, TT-012 inhibits the growth of high-MITF melanoma cells, and inhibits the tumor growth and metastasis with tolerable toxicity to liver and immune cells in animal models. Together, this study demonstrates a unique hyperdynamic dimer interface in melanoma oncoprotein MITF, and reveals a novel approach to therapeutically suppress MITF activity. PubMed: 36588115DOI: 10.1038/s41422-022-00744-5 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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