Title:NMR-based Drug Development and Improvement Against Malignant Melanoma – Implications for the MIA Protein Family
Volume: 24
Issue: 17
Author(s): Oliver Arnolds, Xueyin Zhong, King Tuo Yip, Miriam Schöpel, Bastian Kohl, Stefanie Pütz, Raid Abdel-Jalil and Raphael Stoll*
Affiliation:
- Biomolecular NMR, Ruhr University of Bochum, 44780 Bochum,Germany
Keywords:
NMR, FBLS, MIA, FDP, TANGO, SH3.
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.
