The
exchange protein activated by cAMP (EPAC) is a promising drug
target for a wide disease range, from neurodegeneration and infections
to cancer and cardiovascular conditions. A novel partial agonist of
the EPAC isoform 1 (EPAC1), I942, was recently discovered, but its
mechanism of action remains poorly understood. Here, we utilize NMR
spectroscopy to map the I942–EPAC1 interactions at atomic resolution
and propose a mechanism for I942 partial agonism. We found that I942
interacts with the phosphate binding cassette (PBC) and base binding
region (BBR) of EPAC1, similar to cyclic adenosine monophosphate (cAMP).
These results not only reveal the molecular basis for the I942 vs
cAMP mimicry and competition, but also suggest that the partial agonism
of I942 arises from its ability to stabilize an inhibition-incompetent
activation intermediate distinct from both active and inactive EPAC1
states. The mechanism of action of I942 may facilitate drug design
for EPAC-related diseases.
Motivation
Correlated NMR chemical shift changes identified through the CHEmical Shift Projection Analysis (CHESPA) and CHEmical Shift Covariance Analysis (CHESCA) reveal pathways of allosteric transitions in biological macromolecules. To address the need for an automated platform that implements CHESPA and CHESCA and integrates them with other NMR analysis software packages, we introduce here integrated plugins for NMRFAM-SPARKY that implement the seamless detection and visualization of allosteric networks.
Availability
CHESCA-SPARKY and CHESPA-SPARKY are available in the latest version of NMRFAM-SPARKY from the National Magnetic Resonance Facility at Madison (http://pine.nmrfam.wisc.edu/download_packages.html), the NMRbox Project (https://nmrbox.org) and to subscribers to the SBGrid (https://sbgrid.org). The assigned spectra involved in this study and tutorial videos using this data set are available at https://sites.google.com/view/chescachespa-sparky.
Supplementary information
Supplementary data are available at Bioinformatics Online.
The biological, therapeutic and medicinal properties of coumarins and its analogs have prompted enormous research aimed at developing synthetic routes to these heterocycles. This review presents a systematic and comprehensive survey of the method of preparation, the chemical reactivity and biological properties associated with this system.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.