7ALV

Crystal Structure of NLRP3 NACHT domain in complex with a potent inhibitor

7ALV の概要

• エントリーDOI: 10.2210/pdb7alv/pdb
• 分子名称: NACHT, LRR and PYD domains-containing protein 3, 1-[4-chloranyl-2,6-di(propan-2-yl)phenyl]-3-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-urea, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: inflammasome, immune system
• 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: 65026.46

構造登録者

Dekker, C.,Hinniger, A. (登録日: 2020-10-07, 公開日: 2021-10-20, 最終更新日: 2024-01-31)

主引用文献

Dekker, C.,Mattes, H.,Wright, M.,Boettcher, A.,Hinniger, A.,Hughes, N.,Kapps-Fouthier, S.,Eder, J.,Erbel, P.,Stiefl, N.,Mackay, A.,Farady, C.J.
Crystal Structure of NLRP3 NACHT Domain With an Inhibitor Defines Mechanism of Inflammasome Inhibition.
J.Mol.Biol., 433:167309-167309, 2021

PubMed Abstract: The NLRP3 inflammasome assembles in response to a variety of pathogenic and sterile danger signals, resulting in the production of interleukin-1β and interleukin-18. NLRP3 is a key component of the innate immune system and has been implicated as a driver of a number of acute and chronic diseases. We report the 2.8 Å crystal structure of the NLRP3 NACHT domain in complex with an inhibitor. The structure defines a binding pocket formed by the four subdomains of the NACHT domain, and shows the inhibitor acts as an intramolecular glue, which locks the protein in an inactive conformation. It provides further molecular insight into our understanding of NLRP3 activation, helps to detail the residues involved in subdomain coordination within the NLRP3 NACHT domain, and gives molecular insights into how gain-of-function mutations de-stabilize the inactive conformation of NLRP3. Finally, it suggests stabilizing the auto-inhibited form of the NACHT domain is an effective way to inhibit NLRP3, and will aid the structure-based development of NLRP3 inhibitors for a range of inflammatory diseases.

PubMed: 34687713
DOI: 10.1016/j.jmb.2021.167309

実験手法

X-RAY DIFFRACTION (2.835 Å)