Structural basis of adenylyl cyclase 9 activation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
24 02 2022
24 02 2022
Historique:
received:
24
08
2021
accepted:
31
01
2022
entrez:
25
2
2022
pubmed:
26
2
2022
medline:
13
4
2022
Statut:
epublish
Résumé
Adenylyl cyclase 9 (AC9) is a membrane-bound enzyme that converts ATP into cAMP. The enzyme is weakly activated by forskolin, fully activated by the G protein Gαs subunit and is autoinhibited by the AC9 C-terminus. Although our recent structural studies of the AC9-Gαs complex provided the framework for understanding AC9 autoinhibition, the conformational changes that AC9 undergoes in response to activator binding remains poorly understood. Here, we present the cryo-EM structures of AC9 in several distinct states: (i) AC9 bound to a nucleotide inhibitor MANT-GTP, (ii) bound to an artificial activator (DARPin C4) and MANT-GTP, (iii) bound to DARPin C4 and a nucleotide analogue ATPαS, (iv) bound to Gαs and MANT-GTP. The artificial activator DARPin C4 partially activates AC9 by binding at a site that overlaps with the Gαs binding site. Together with the previously observed occluded and forskolin-bound conformations, structural comparisons of AC9 in the four conformations described here show that secondary structure rearrangements in the region surrounding the forskolin binding site are essential for AC9 activation.
Identifiants
pubmed: 35210418
doi: 10.1038/s41467-022-28685-y
pii: 10.1038/s41467-022-28685-y
pmc: PMC8873477
doi:
Substances chimiques
Nucleotides
0
Colforsin
1F7A44V6OU
Guanosine Triphosphate
86-01-1
Adenylyl Cyclases
EC 4.6.1.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1045Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM060419
Pays : United States
Informations de copyright
© 2022. The Author(s).
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