NMR-based Drug Development and Improvement Against Malignant Melanoma – Implications for the MIA Protein Family

Abstract

The Melanoma Inhibitory Activity (MIA) protein is strongly expressed and secreted by malignant melanoma cells and was shown to promote melanoma development and invasion. The MIA protein was the first extracellular protein shown to adopt an Src homology 3 (SH3) domain-like fold in solution that can bind to fibronectin type III domains. Together with MIA, the homologous proteins OTOR (or FDP), MIA-2, and TANGO (or MIA-3) constitute a protein family of non-cytosolic and - except for fulllength TANGO and TANGO1-like (TALI) - extracellular SH3-domain containing proteins. Members of this protein family modulate collagen maturation and export, cartilage development, cell attachment in the extracellular matrix, and melanoma metastasis. These proteins may thus serve as promising targets for drug development against malignant melanoma. For the last twenty years, NMR spectroscopy has become a powerful technique in medicinal chemistry. While traditional high throughput screenings only report on the activity or affinity of low molecular weight compounds, NMR spectroscopy does not only relate to the structure of those compounds with their activity, but it can also unravel structural information on the ligand binding site on the protein at atomic resolution. Based on the molecular details of the interaction between the ligand and its target protein, the binding affinities of initial fragment hits can be further improved more efficiently in order to generate lead structures that exhibit significant therapeutic effects. The NMR-based approach promises to greatly contribute to the quest for low molecular weight compounds that ultimately could yield drugs to treat skin-related diseases such as malignant melanoma more effectively.

Characterization of a fold in TANGO1 evolved from SH3 domains for the export of bulky cargos

“…These supplementary structural elements have already been observed in a similar fashion for the MIA protein 18,19 and are presumably present in other members of this domain family, i.e., TALI and Otoraplin, as judged from multiple sequence alignments (Fig. 1b) 20 .…”

“…The TANGO1 protein family is encoded by genes of the mia family (mia, mia2, mia3, and mial1), all of which either consist of or carry a homologous domain described as an SH3 domain 20 . The eponymous MIA protein is an extracellular homologue to the cargo-recognition domains of TANGO1 and TALI, and has already been shown not to interact with classical PPII ligands of SH3 domains 19 .…”

A new fold in TANGO1 evolved from SH3 domains for the export of bulky cargos

“…The TANGO1 protein family is encoded by genes of the mia family ( mia, mia2, mia3 , and mial1 ), all of which either consist of or carry a homologous domain described as an SH3 domain. 20 The eponymous MIA protein is an extracellular homologue to the cargo-recognition domains of TANGO1 and TALI, and has already been shown not to interact with classical PPII ligands of SH3 domains. 19 Due to the sequential and structural similarities of the cargo-recognition domains of the TANGO1 protein family with SH3 domains, we investigated their capability to interact with class I and II PPII helices that correspond to the recognition sequences of classical SH3 domains.…”

The Role of Biomarkers in the Diagnosis and Prognosis of Different Stages of Melanoma

“…In addition to clinical markers, imaging techniques such as ultrasonography, magnetic resonance imaging (MRI), and computed tomography (CT) scans can aid in diagnosing melanoma. Ultrasonography is useful for assessing the thickness of melanomas, while MRI and CT scans can provide detailed images of the internal structures of the skin and surrounding tissue, as well as rule out metastasis to other organs [1,[3][4][5][6][7][8][16][17][18][19][20][21][22][23].…”

“…Early detection and prevention through sun protection are critical in reducing the morbidity and mortality associated with melanoma. Therefore, identifying biomarkers associated with the disease has therapeutic and prognostic implications, particularly in advanced-stage melanoma, where early diagnosis and treatment can lead to high survival rates [1][2][3][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31]. In this article, we will discuss current methods of melanoma diagnosis, including clinical markers, imaging, and histopathological examination.…”