Crystal structure of the catalytic D2 domain of the AAA + ATPase p97 reveals a putative helical split‐washer‐type mechanism for substrate unfolding

DOI: 10.1002/1873-3468.13667

Authors: Lasse Stach (Imperial College London) , R. Marc Morgan (Imperial College London) , Linda Makhlouf (Imperial College London) , Alice Douangamath (Diamond Light Source) , Frank Von Delft (Diamond Light Source) , Xiaodong Zhang (Imperial College London) , Paul S. Freemont (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Febs Letters

State: Published (Approved)
Published: November 2019
Diamond Proposal Number(s): 16980

Abstract: Several pathologies have been associated with the AAA + ATPase p97, an enzyme essential to protein homeostasis. Heterozygous polymorphisms in p97 have been shown to cause neurological disease, while elevated proteotoxic stress in tumours has made p97 an attractive cancer chemotherapy target. The cellular processes reliant on p97 are well described. High‐resolution structural models of its catalytic D2 domain, however, have proved elusive, as has the mechanism by which p97 converts the energy from ATP hydrolysis into mechanical force to unfold protein substrates. Here, we describe the high‐resolution structure of the p97 D2 ATPase domain. This crystal system constitutes a valuable tool for p97 inhibitor development and identifies a potentially druggable pocket in the D2 domain. In addition, its P61 symmetry suggests a mechanism for substrate unfolding by p97.

Journal Keywords: AAA+ ATPase; D2 domain; IBMPFD; p97

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Diamond Offline Facilities: XChem
Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 12/11/2019 14:24

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening