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PDBsum entry 5ftj
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References listed in PDB file
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Key reference
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Title
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2.3 å resolution cryo-Em structure of human p97 and mechanism of allosteric inhibition.
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Authors
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S.Banerjee,
A.Bartesaghi,
A.Merk,
P.Rao,
S.L.Bulfer,
Y.Yan,
N.Green,
B.Mroczkowski,
R.J.Neitz,
P.Wipf,
V.Falconieri,
R.J.Deshaies,
J.L.Milne,
D.Huryn,
M.Arkin,
S.Subramaniam.
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Ref.
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Science, 2016,
351,
871-875.
[DOI no: ]
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PubMed id
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Abstract
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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.
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