7d8t
MITF bHLHLZ complex with M-box DNA
Structural highlights
DiseaseMITF_HUMAN MITF-related melanoma and renal cell carcinoma predisposition syndrome;Clear cell renal carcinoma;Papillary renal cell carcinoma;Tietz syndrome;Waardenburg syndrome type 2;Ocular albinism with congenital sensorineural deafness. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. FunctionMITF_HUMAN Transcription factor that regulates the expression of genes with essential roles in cell differentiation, proliferation and survival. Binds to symmetrical DNA sequences (E-boxes) (5'-CACGTG-3') found in the promoters of target genes, such as BCL2 and tyrosinase (TYR). Plays an important role in melanocyte development by regulating the expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TYRP1). Plays a critical role in the differentiation of various cell types, such as neural crest-derived melanocytes, mast cells, osteoclasts and optic cup-derived retinal pigment epithelium.[1] [2] O66738_AQUAE Publication Abstract from PubMedMicrophthalmia 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. A unique hyperdynamic dimer interface permits small molecule perturbation of the melanoma oncoprotein MITF for melanoma therapy.,Liu Z, Chen K, Dai J, Xu P, Sun W, Liu W, Zhao Z, Bennett SP, Li P, Ma T, Lin Y, Kawakami A, Yu J, Wang F, Wang C, Li M, Chase P, Hodder P, Spicer TP, Scampavia L, Cao C, Pan L, Dong J, Chen Y, Yu B, Guo M, Fang P, Fisher DE, Wang J Cell Res. 2023 Jan;33(1):55-70. doi: 10.1038/s41422-022-00744-5. Epub 2023 Jan 2. PMID:36588115[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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