4A6E

Crystal structure of human N-acetylserotonin methyltransferase (ASMT) in complex with SAM and N-acetylserotonin

4A6E の概要

• エントリーDOI: 10.2210/pdb4a6e/pdb
• 関連するPDBエントリー: 4A6D
• 分子名称: HYDROXYINDOLE O-METHYLTRANSFERASE, ZINC ION, S-ADENOSYLMETHIONINE, ... (7 entities in total)
• 機能のキーワード: transferase, melatonin, circadian clock
• 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: 40829.37

構造登録者

Legrand, P.,Haouz, A.,Shepard, W. (登録日: 2011-11-01, 公開日: 2012-11-07, 最終更新日: 2024-05-08)

主引用文献

Botros, H.G.,Legrand, P.,Pagan, C.,Bondet, V.,Weber, P.,Ben-Abdallah, M.,Lemiere, N.,Huguet, G.,Bellalou, J.,Maronde, E.,Beguin, P.,Haouz, A.,Shepard, W.,Bourgeron, T.
Crystal Structure and Functional Mapping of Human Asmt, the Last Enzyme of the Melatonin Synthesis Pathway.
J.Pineal Res., 54:46-, 2013

PubMed Abstract: Melatonin is a synchronizer of many physiological processes. Abnormal melatonin signaling is associated with human disorders related to sleep, metabolism, and neurodevelopment. Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. The polypeptide chain of ASMT consists of a C-terminal domain, which is typical of other SAM-dependent O-methyltransferases, and an N-terminal domain, which intertwines several helices with another monomer to form the physiologically active dimer. Using radioenzymology, we analyzed 20 nonsynonymous variants identified through the 1000 genomes project and in patients with neuropsychiatric disorders. We found that the majority of these mutations reduced or abolished ASMT activity including one relatively frequent polymorphism in the Han Chinese population (N17K, rs17149149). Overall, we estimate that the allelic frequency of ASMT deleterious mutations ranges from 0.66% in Europe to 2.97% in Asia. Mapping of the variants on to the 3-dimensional structure clarifies why some are harmful and provides a structural basis for understanding melatonin deficiency in humans.

PubMed: 22775292
DOI: 10.1111/J.1600-079X.2012.01020.X

実験手法

X-RAY DIFFRACTION (2.7 Å)