5FTN: Cryo-em Structure Of Human P97 Bound To Atpgs (conformation Iii)

Citation:
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) (ATPgammaS) per protomer. A large corkscrew-like change in molecular architecture, coupled with upward displacement of the N-terminal domain, is observed only when ATPgammaS 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.
PDB ID: 5FTNDownload
MMDB ID: 136082
PDB Deposition Date: 2016/1/14
Updated in MMDB: 2016/03
Experimental Method:
electron microscopy
Resolution: 3.3  Å
Source Organism:
Similar Structures:
Biological Unit for 5FTN: hexameric; determined by author and by software (PISA)
Molecular Components in 5FTN
Label Count Molecule
Proteins (6 molecules)
6
Transitional Endoplasmic Reticulum Atpase(Gene symbol: VCP)
Molecule annotation
Chemicals (24 molecules)
1
12
2
12
* Click molecule labels to explore molecular sequence information.

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