7PWY

Structure of human dimeric ACMSD in complex with the inhibitor TES-1025

7PWY の概要

• エントリーDOI: 10.2210/pdb7pwy/pdb
• 分子名称: 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase, ZINC ION, 2-[3-[(5-cyano-6-oxidanylidene-4-thiophen-2-yl-1H-pyrimidin-2-yl)sulfanylmethyl]phenyl]ethanoic acid, ... (5 entities in total)
• 機能のキーワード: acmsd, de-novo nad+ synthesis, tes-1025, decarboxylase, lyase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 153600.00

構造登録者

Cianci, M.,Giacche, N.,Carotti, A.,Liscio, P.,Amici, A.,Cialabrini, L.,De Franco, F.,Pellicciari, R.,Raffaelli, N. (登録日: 2021-10-07, 公開日: 2022-04-20, 最終更新日: 2024-01-31)

主引用文献

Cianci, M.,Giacche, N.,Cialabrini, L.,Carotti, A.,Liscio, P.,Rosatelli, E.,De Franco, F.,Gasparrini, M.,Robertson, J.,Amici, A.,Raffaelli, N.,Pellicciari, R.
Structural Basis of Human Dimeric alpha-Amino-beta-Carboxymuconate-epsilon-Semialdehyde Decarboxylase Inhibition With TES-1025.
Front Mol Biosci, 9:834700-834700, 2022

PubMed Abstract: Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) stands at a branch point of the NAD synthesis pathway and plays an important role in maintaining NAD homeostasis. It has been recently identified as a novel therapeutic target for a wide range of diseases, including inflammatory, metabolic disorders, and aging. So far, in absence of potent and selective enzyme inhibitors, only a crystal structure of the complex of human dimeric ACMSD with pseudo-substrate dipicolinic acid has been resolved. In this study, we report the crystal structure of the complex of human dimeric ACMSD with TES-1025, the first nanomolar inhibitor of this target, which shows a binding conformation different from the previously published predicted binding mode obtained by docking experiments. The inhibitor has a value of 0.85 ± 0.22 nM and binds in the catalytic site, interacting with the Zn metal ion and with residues belonging to both chains of the dimer. The results provide new structural information about the mechanism of inhibition exerted by a novel class of compounds on the ACMSD enzyme, a novel therapeutic target for liver and kidney diseases.

PubMed: 35463964
DOI: 10.3389/fmolb.2022.834700

実験手法

X-RAY DIFFRACTION (2.5 Å)