5FTK

Cryo-EM structure of human p97 bound to ADP

Summary for 5FTK

• Entry DOI: 10.2210/pdb5ftk/pdb
• Related: 5FTJ 5FTL 5FTM 5FTN
• EMDB information: 3296
• Descriptor: TRANSITIONAL ENDOPLASMIC RETICULUM ATPASE, ADENOSINE-5'-DIPHOSPHATE (3 entities in total)
• Functional Keywords: hydrolase, single-particle, p97, aaa atpase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 6
• Total formula weight: 541747.33

Authors

Banerjee, S.,Bartesaghi, A.,Merk, A.,Rao, P.,Bulfer, S.L.,Yan, Y.,Green, N.,Mroczkowski, B.,Neitz, R.J.,Wipf, P.,Falconieri, V.,Deshaies, R.J.,Milne, J.L.S.,Huryn, D.,Arkin, M.,Subramaniam, S. (deposition date: 2016-01-14, release date: 2016-01-27, Last modification date: 2024-05-08)

Primary citation

Banerjee, S.,Bartesaghi, A.,Merk, A.,Rao, P.,Bulfer, S.L.,Yan, Y.,Green, N.,Mroczkowski, B.,Neitz, R.J.,Wipf, P.,Falconieri, V.,Deshaies, R.J.,Milne, J.L.S.,Huryn, D.,Arkin, M.,Subramaniam, S.
2.3 A Resolution Cryo-Em Structure of Human P97 and Mechanism of Allosteric Inhibition
Science, 351:871-, 2016

PubMed Abstract: 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.

PubMed: 26822609
DOI: 10.1126/SCIENCE.AAD7974

Experimental method

ELECTRON MICROSCOPY (2.4 Å)