A Non‐Competitive Inhibitor of VCP/p97 and VPS4 Reveals Conserved Allosteric Circuits in Type I and II AAA ATPases

Abstract

AAA ATPases have pivotal functions in diverse cellular processes essential for survival and proliferation. Revealing strategies for chemical inhibition of this class of enzymes is therefore of great interest for the development of novel chemotherapies or chemical tools.Here,wecharacterize the compound MSC1094308 as areversible,allosteric inhibitor of the type II AAA ATPase human ubiquitin-directed unfoldase (VCP)/p97 and the type IA AA ATPase VPS4B. Subsequent proteomic, genetic and biochemical studies indicate that MSC1094308 binds to ap reviously characterized drugable hotspot of p97, therebyi nhibiting the D2 ATPase activity.O ur results furthermore indicate that as imilar allosteric site exists in VPS4B,s uggesting conserved allosteric circuits and drugable sites in both type Iand II AAA ATPases. Our results mayt hus guide future chemical tool and drug discovery efforts for the biomedically relevant AAA ATPases.

Small-Molecule Modulators of the ATPase VCP/p97 Affect Specific p97 Cellular Functions

“…8,9 Several inhibitors of the D2 ATPase domain of p97 are available. 15−21 The most used p97 inhibitors identified recently, DBeQ, NMS-873, and MSC1094308, 16,19,20 were isolated by screening compounds that inhibit the ATPase activity in vitro. Since p97 participates in a wide range of cellular processes, treatment with these drugs causes major cellular defects, including cell death.…”