Details

Autor(en) / Beteiligte

• Banerjee, Soojay
• Bartesaghi, Alberto
• Merk, Alan
• Rao, Prashant
• Bulfer, Stacie L.
• Yan, Yongzhao
• Green, Neal
• Mroczkowski, Barbara
• Neitz, R. Jeffrey
• Wipf, Peter
• Falconieri, Veronica
• Deshaies, Raymond J.
• Milne, Jacqueline L. S.
• Huryn, Donna
• Arkin, Michelle
• Subramaniam, Sriram

Titel

2.3 Å resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition

Ist Teil von

• Science (American Association for the Advancement of Science), 2016-02, Vol.351 (6275), p.871-875

Ort / Verlag

United States: American Association for the Advancement of Science

Erscheinungsjahr

2016

Quelle

Science Online_科学在线

Beschreibungen/Notizen

• p97 is a hexameric AAA+ adenosine triphosphatase (ATPase) that is an attractive target for cancer drug development. We report cryo–electron microscopy (cryo-EM) structures for adenosine diphosphate (ADP)–bound, full-length, hexameric wild-type p97 in the presence and absence of an allosteric inhibitor at resolutions of 2.3 and 2.4 angstroms, respectively. We also report cryo-EM structures (at resolutions of ~3.3, 3.2, and 3.3 angstroms, respectively) for three distinct, coexisting functional states of p97 with occupancies of zero, one, or two molecules of adenosine 5′-O-(3-thiotriphosphate) (ATPγS) per protomer. A large corkscrew-like change in molecular architecture, coupled with upward displacement of the N-terminal domain, is observed only when ATPγS is bound to both the D1 and D2 domains of the protomer. These cryo-EM structures establish the sequence of nucleotide-driven structural changes in p97 at atomic resolution. They also enable elucidation of the binding mode of an allosteric small-molecule inhibitor to p97 and illustrate how inhibitor binding at the interface between the D1 and D2 domains prevents propagation of the conformational changes necessary for p97 function.