8VLS

Structure of VCP in complex with an ATPase activator (D2 domains only, dodecameric form)

これはPDB形式変換不可エントリーです。

8VLS の概要

• エントリーDOI: 10.2210/pdb8vls/pdb
• EMDBエントリー: 43329 43343 43392
• 分子名称: Transitional endoplasmic reticulum ATPase, (3R)-N-[2-(ethylsulfanyl)phenyl]-3-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)butanamide (2 entities in total)
• 機能のキーワード: activator, complex, atpase, aaa protein, hydrolase, hydrolase-activator complex, hydrolase/activator
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 1077495.43

構造登録者

Jones, N.H.,Urnivicius, L.,Kapoor, T.M. (登録日: 2024-01-12, 公開日: 2024-06-19)

主引用文献

Jones, N.H.,Liu, Q.,Urnavicius, L.,Dahan, N.E.,Vostal, L.E.,Kapoor, T.M.
Allosteric activation of VCP, an AAA unfoldase, by small molecule mimicry.
Proc.Natl.Acad.Sci.USA, 121:e2316892121-e2316892121, 2024

PubMed Abstract: The loss of function of AAA (ATPases associated with diverse cellular activities) mechanoenzymes has been linked to diseases, and small molecules that activate these proteins can be powerful tools to probe mechanisms and test therapeutic hypotheses. Unlike chemical inhibitors that can bind a single conformational state to block enzyme function, activator binding must be permissive to different conformational states needed for mechanochemistry. However, we do not know how AAA proteins can be activated by small molecules. Here, we focus on valosin-containing protein (VCP)/p97, an AAA unfoldase whose loss of function has been linked to protein aggregation-based disorders, to identify druggable sites for chemical activators. We identified VCP ATPase Activator 1 (VAA1), a compound that dose-dependently stimulates VCP ATPase activity up to ~threefold. Our cryo-EM studies resulted in structures (ranging from ~2.9 to 3.7 Å-resolution) of VCP in apo and ADP-bound states and revealed that VAA1 binds an allosteric pocket near the C-terminus in both states. Engineered mutations in the VAA1-binding site confer resistance to VAA1, and furthermore, modulate VCP activity. Mutation of a phenylalanine residue in the VCP C-terminal tail that can occupy the VAA1 binding site also stimulates ATPase activity, suggesting that VAA1 acts by mimicking this interaction. Together, our findings uncover a druggable allosteric site and a mechanism of enzyme regulation that can be tuned through small molecule mimicry.

PubMed: 38833472
DOI: 10.1073/pnas.2316892121

実験手法

ELECTRON MICROSCOPY (2.9 Å)