9EY5

Crystal structure of human tyrosinase-related protein 1 (TYRP1) in complex with (S)-2,4-dihydroxyphenylalanine

9EY5 の概要

• エントリーDOI: 10.2210/pdb9ey5/pdb
• 分子名称: 5,6-dihydroxyindole-2-carboxylic acid oxidase, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: melanogenesis, human tyrosinase, tyrosinase inhibitor, metal binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 54225.07

構造登録者

Ng, Y.M.,Soler-Lopez, M. (登録日: 2024-04-09, 公開日: 2024-05-22, 最終更新日: 2024-07-03)

主引用文献

Faure, C.,Min Ng, Y.,Belle, C.,Soler-Lopez, M.,Khettabi, L.,Saidi, M.,Berthet, N.,Maresca, M.,Philouze, C.,Rachidi, W.,Reglier, M.,du Moulinet d'Hardemare, A.,Jamet, H.
Interactions of Phenylalanine Derivatives with Human Tyrosinase: Lessons from Experimental and Theoretical tudies.
Chembiochem, 25:e202400235-e202400235, 2024

PubMed Abstract: The pigmentation of the skin, modulated by different actors in melanogenesis, is mainly due to the melanins (protective pigments). In humans, these pigments' precursors are synthetized by an enzyme known as tyrosinase (TyH). The regulation of the enzyme activity by specific modulators (inhibitors or activators) can offer a means to fight hypo- and hyper-pigmentations responsible for medical, psychological and societal handicaps. Herein, we report the investigation of phenylalanine derivatives as TyH modulators. Interacting with the binuclear copper active site of the enzyme, phenylalanine derivatives combine effects induced by combination with known resorcinol inhibitors and natural substrate/intermediate (amino acid part). Computational studies including docking, molecular dynamics and free energy calculations combined with biological activity assays on isolated TyH and in human melanoma MNT-1 cells, and X-ray crystallography analyses with the TyH analogue Tyrp1, provide conclusive evidence of the interactions of phenylalanine derivatives with human tyrosinase. In particular, our findings indicate that an analogue of L-DOPA, namely (S)-3-amino-tyrosine, stands out as an amino phenol derivative with inhibitory properties against TyH.

PubMed: 38642076
DOI: 10.1002/cbic.202400235

実験手法

X-RAY DIFFRACTION (2.61 Å)