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Shein, M. ; Hitzenberger, M.* ; Cheng, T.C.* ; Rout, S.R.* ; Leitl, K. ; Sato, Y.* ; Zacharias, M.* ; Sakata, E.* ; Schütz, A.K.

Characterizing ATP processing by the AAA+ protein p97 at the atomic level.

Nat. Chem. 16, 363-372 (2024)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
The human enzyme p97 regulates various cellular pathways by unfolding hundreds of protein substrates in an ATP-dependent manner, making it an essential component of protein homeostasis and an impactful pharmacological target. The hexameric complex undergoes substantial conformational changes throughout its catalytic cycle. Here we elucidate the molecular motions that occur at the active site in the temporal window immediately before and after ATP hydrolysis by merging cryo-EM, NMR spectroscopy and molecular dynamics simulations. p97 populates a metastable reaction intermediate, the ADP·Pi state, which is poised between hydrolysis and product release. Detailed snapshots reveal that the active site is finely tuned to trap and eventually discharge the cleaved phosphate. Signalling pathways originating at the active site coordinate the action of the hexamer subunits and couple hydrolysis with allosteric conformational changes. Our multidisciplinary approach enables a glimpse into the sophisticated spatial and temporal orchestration of ATP handling by a prototype AAA+ protein.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Molecular-dynamics Simulations; Structural Basis; Cryo-em; Active-site; Hydrolysis; Mechanism; Software; Amber; Visualization; Parameters
ISSN (print) / ISBN 1755-4330
e-ISSN 1755-4349
Zeitschrift Nature chemistry
Quellenangaben Band: 16, Heft: 3, Seiten: 363-372 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
Förderungen
German Research Foundation (DFG)