7KZE

Substrate-dependent divergence of leukotriene A4 hydrolase aminopeptidase activity

7KZE の概要

• エントリーDOI: 10.2210/pdb7kze/pdb
• 分子名称: Leukotriene A-4 hydrolase, ZINC ION, 1-benzyl-4-methoxybenzene, ... (5 entities in total)
• 機能のキーワード: leukotriene a4 hydrolase, 4mdm, aminipeptidase, activator, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 207762.56

構造登録者

Lee, K.H.,Shim, Y.,Paige, M.,Noble, S.M. (登録日: 2020-12-10, 公開日: 2022-06-15, 最終更新日: 2023-10-18)

主引用文献

Lee, K.H.,Ali, N.F.,Lee, S.H.,Zhang, Z.,Burdick, M.,Beaulac, Z.J.,Petruncio, G.,Li, L.,Xiang, J.,Chung, E.M.,Foreman, K.W.,Noble, S.M.,Shim, Y.M.,Paige, M.
Substrate-dependent modulation of the leukotriene A 4 hydrolase aminopeptidase activity and effect in a murine model of acute lung inflammation.
Sci Rep, 12:9443-9443, 2022

PubMed Abstract: The aminopeptidase activity (AP) of the leukotriene A hydrolase (LTAH) enzyme has emerged as a therapeutic target to modulate host immunity. Initial reports focused on the benefits of augmenting the LTAH AP activity and clearing its putative pro-inflammatory substrate Pro-Gly-Pro (PGP). However, recent reports have introduced substantial complexity disconnecting the LTAH modulator 4-methoxydiphenylmethane (4MDM) from PGP as follows: (1) 4MDM inhibits PGP hydrolysis and subsequently inhibition of LTAH AP activity, and (2) 4MDM activates the same enzyme target in the presence of alternative substrates. Differential modulation of LTAH by 4MDM was probed in a murine model of acute lung inflammation, which showed that 4MDM modulates the host neutrophilic response independent of clearing PGP. X-ray crystallography showed that 4MDM and PGP bind at the zinc binding pocket and no allosteric binding was observed. We then determined that 4MDM modulation is not dependent on the allosteric binding of the ligand, but on the N-terminal side chain of the peptide. In conclusion, our study revealed that a peptidase therapeutic target can interact with its substrate and ligand in complex biochemical mechanisms. This raises an important consideration when ligands are designed to explain some of the unpredictable outcomes observed in therapeutic discovery targeting LTAH.

PubMed: 35676292
DOI: 10.1038/s41598-022-13238-6

実験手法

X-RAY DIFFRACTION (2.9 Å)