Laboratory of Biophysical Chemistry, University of Groningen, 9717 GA Groningen, The Netherlands.
European Synchrotron Radiation Facility, 38043 Grenoble, France.
Int J Mol Sci. 2020 Jan 30;21(3):915. doi: 10.3390/ijms21030915.
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.
酪氨酸酶相关蛋白 1（TYRP1）是参与黑色素生物合成的三种人类黑色素生成酶之一，黑色素是决定皮肤、头发和眼睛颜色的色素。它与酪氨酸酶具有高度的序列同一性，但在其活性位点有两个锌离子，而不是酪氨酸酶中的两个铜离子。典型的酪氨酸酶抑制剂不能直接与 TYRP1 的锌离子配位。在这里，我们通过 X 射线晶体结构测定表明，苯硫脲是一种高效的酪氨酸酶抑制剂，它既不与活性位点的锌离子配位，也与其他结构特征明确的 TYRP1 抑制剂复合物不同。它的芳环从活性位点向外定向，显然是由于缺乏可以取代结合在活性位点的水分子的极性氧取代基。该化合物通过疏水相互作用结合，从而阻止底物进入活性位点。
