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Title | 2.3 Å resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition. |
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Journal, issue, pages | Science, Vol. 351, Issue 6275, Page 871-875, Year 2016 |
Publish date | Feb 19, 2016 |
Authors | Soojay Banerjee / Alberto Bartesaghi / Alan Merk / Prashant Rao / Stacie L Bulfer / Yongzhao Yan / Neal Green / Barbara Mroczkowski / R Jeffrey Neitz / Peter Wipf / Veronica Falconieri / Raymond J Deshaies / Jacqueline L S Milne / Donna Huryn / Michelle Arkin / Sriram Subramaniam / |
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 ...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. |
External links | Science / PubMed:26822609 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.3 - 3.3 Å |
Structure data | EMDB-3295: Cryo-EM structure of human p97 bound UPCDC30245 inhibitor EMDB-3296, PDB-5ftk: EMDB-3297, PDB-5ftl: |
Chemicals | ChemComp-ADP: ChemComp-OJA: ChemComp-HOH: ChemComp-AGS: ChemComp-MG: |
Source |
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Keywords | HYDROLASE / SINGLE-PARTICLE / P97 / AAA ATPASE |