|Title||Phenylthiourea binding to human tyrosinase-related protein 1|
|Author(s)||Lai, Xuelei; Wichers, Harry J.; Soler-Lopez, Montserrat; Dijkstra, Bauke W.|
|Source||International Journal of Molecular Sciences 21 (2020)3. - ISSN 1661-6596|
Food, Health & Consumer Research
|Publication type||Refereed Article in a scientific journal|
|Keyword(s)||Albinism - Crystal structure - Human tyrosinase - Human tyrosinase-related protein - Inhibitor - Melanogenesis - N-glycosylation - Phenylthiourea - Zinc-Copper enzymes|
Tyrosinase-related protein 1 (TYRP1) is one of the three human melanogenic enzymes involved in the biosynthesis of melanin, a pigment responsible for the color of the skin, hair, and eyes. It shares high sequence identity with tyrosinase, but has two zinc ions in its active site rather than two copper ions as in tyrosinase. Typical tyrosinase inhibitors do not directly coordinate to the zinc ions of TYRP1. Here, we show, from an X-ray crystal structure determination, that phenylthiourea, a highly potent tyrosinase inhibitor, does neither coordinate the active site zinc ions, but binds differently from other structurally characterized TYRP1-inhibitor complexes. Its aromatic ring is directed outwards from the active site, apparently as a result from the absence of polar oxygen substituents that can take the position of water molecules bound in the active site. The compound binds via hydrophobic interactions, thereby blocking substrate access to the active site.