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

• Published in: Angewandte Chemie Vol. 130; no. 6; pp. 1592 - 1596
• Main Authors: Pöhler, Robert, Krahn, Jan H., van den Boom, Johannes, Dobrynin, Grzegorz, Kaschani, Farnusch, Eggenweiler, Hans‐Michael, Zenke, Frank T., Kaiser, Markus, Meyer, Hemmo
• Format: Journal Article
• Language: English; German
• Published: Weinheim Wiley Subscription Services, Inc 05.02.2018
• Subjects: AAA-ATPase; Adenosine triphosphatase; Allosteric properties; Allosterie; Chemistry; Circuits; Drug discovery; Inhibitors; p97; Ubiquitin; VPS4; Wirkstoffentwicklung
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201711429

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, we characterize the compound MSC1094308 as a reversible, allosteric inhibitor of the type II AAA ATPase human ubiquitin‐directed unfoldase (VCP)/p97 and the type I AAA ATPase VPS4B. Subsequent proteomic, genetic and biochemical studies indicate that MSC1094308 binds to a previously characterized drugable hotspot of p97, thereby inhibiting the D2 ATPase activity. Our results furthermore indicate that a similar allosteric site exists in VPS4B, suggesting conserved allosteric circuits and drugable sites in both type I and II AAA ATPases. Our results may thus guide future chemical tool and drug discovery efforts for the biomedically relevant AAA ATPases. Einer für alles: Die niedermolekulare Verbindung MSC1094308 (siehe Bild) wirkt als allosterischer Inhibitor der Typ‐I‐AAA‐ATPase VPS4B und der Typ‐II‐AAA‐ATPase p97. Die Ergebnisse sprechen für die Existenz von unerwarteten konservierten allosterischen Regionen in den beiden architektonisch diversen AAA‐ATPasen.