Structure and Function of Adenylyl Cyclase
EMSL Project ID
50470
Abstract
Adenylyl cyclases (ACs) are a family of proteins that convert ATP to the second messenger cyclic AMP (cAMP). They are widely expressed and involved in numerous biological processes. The transmembrane ACs are one of the main effectors of G protein-coupled receptor signal transduction pathways. Activated alpha and beta-gamma subunits of heterotrimeric G proteins interact directly with ACs and can have either stimulatory or inhibitory effects, depending on both the AC and G protein subtypes that are involved. Our understanding of the molecular mechanisms that underlie these various forms of functional regulation is severely limited due to a lack of structural information. Our long-term goals are to: 1) Determine the first structure of a full-length transmembrane AC. This will show the overall architecture of the whole protein including the arrangement of all the known G protein-interacting regions as well as start to explain the role of the mysterious transmembrane domains. 2) Determine the structure of a full-length transmembrane AC in complex with G-alphas and the small molecule activator forskolin. This will show for the first time the molecular mechanisms of how G-alphas binding stimulates cAMP production. The structure of the forskolin complex will explain how small molecules can activate the enzyme, which will aid future drug development. 3) Determine structures of ACs in complex with other G proteins. Structures in complex with Gi alpha subunit and G beta-gamma will explain the mechanisms of these forms of regulation and reveal the structural basis for why only some AC subtypes are regulated by these proteins.
Project Details
Start Date
2018-10-30
End Date
2021-01-31
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members