7 research outputs found
Garcinolic Acid Distinguishes Between GACKIX Domains and Modulates Interaction Networks
Natural products are often uniquely suited to modulate protein-protein interactions (PPIs) due to their architectural and functional group complexity relative to synthetic molecules. Here we demonstrate that the natural product garcinolic acid allosterically blocks the CBP/p300 KIX PPI network and displays excellent selectivity over related GACKIX motifs. It does so via a strong interaction (KD 1 μM) with a non-canonical binding site containing a structurally dynamic loop in CBP/p300 KIX. Garcinolic acid engages full-length CBP in the context of the proteome and in doing so effectively inhibits KIX-dependent transcription in a leukemia model. As the most potent small-molecule KIX inhibitor yet reported, garcinolic acid represents an important step forward in the therapeutic targeting of CBP/p300
Inhibition of CREB Binding and Function with a Dual-Targeting Ligand
CBP/p300
is a master transcriptional coactivator that regulates
gene activation by interacting with multiple transcriptional activators.
Dysregulation of protein–protein interactions (PPIs) between
the CBP/p300 KIX domain and its activators is implicated in a number
of cancers, including breast, leukemia, and colorectal cancer. However,
KIX is typically considered “undruggable” because of
its shallow binding surfaces lacking both significant topology and
promiscuous binding profiles. We previously reported a dual-targeting
peptide (MybLL-tide) that inhibits the KIX-Myb interaction with excellent
specificity and potency. Here, we demonstrate a branched, second-generation
analogue, CREBLL-tide, that inhibits the KIX-CREB PPI with higher
potency and selectivity. Additionally, the best of these CREBLL-tide
analogues shows excellent and selective antiproliferation activity
in breast cancer cells. These results indicate that CREBLL-tide is
an effective tool for assessing the role of KIX-activator interactions
in breast cancer and expanding the dual-targeting strategy for inhibiting
KIX and other coactivators that contain multiple binding surfaces
The Nonphysician “Medical Student Educator”: A Formal Addition to the Clerkships and Key Programs at an Academic Medical Center
Image_2_A decade of coral biobanking science in Australia - transitioning into applied reef restoration.tif
Active restoration or intervention programs will be required in the future to support the resilience and adaptation of coral reef ecosystems in the face of climate change. Selective propagation of corals ex situ can help conserve keystone species and the ecosystems they underpin; cross-disciplinary research and communication between science and industry are essential to this success. Zoos and aquaria have a long history of managing ex situ breed-for-release programs and have led the establishment of wildlife biobanks (collections of cryopreserved living cells) along with the development of associated reproductive technologies for their application to wildlife conservation. Taronga Conservation Society Australia’s CryoDiversity Bank includes cryopreserved coral sperm from the Great Barrier Reef, which represents the largest repository from any reef system around the globe. This paper presents results from an inventory review of the current collection. The review highlighted the skew toward five Acropora species and the necessity to increase the taxonomic diversity of the collection. It also highlighted the need to increase geographic representation, even for the most well represented species. The inventory data will inform Taronga’s future research focus and sampling strategy to maximize genetic variation and biodiversity within the biobank and provide a test case for other practitioners implementing biobanking strategies for coral conservation around the world. Through co-investment and collaboration with research partners over the next decade, Taronga will prioritize and resource critical applied research and expand biobanking efforts to assist interventions for reef recovery and restoration.</p
DataSheet_1_A decade of coral biobanking science in Australia - transitioning into applied reef restoration.xlsx
Active restoration or intervention programs will be required in the future to support the resilience and adaptation of coral reef ecosystems in the face of climate change. Selective propagation of corals ex situ can help conserve keystone species and the ecosystems they underpin; cross-disciplinary research and communication between science and industry are essential to this success. Zoos and aquaria have a long history of managing ex situ breed-for-release programs and have led the establishment of wildlife biobanks (collections of cryopreserved living cells) along with the development of associated reproductive technologies for their application to wildlife conservation. Taronga Conservation Society Australia’s CryoDiversity Bank includes cryopreserved coral sperm from the Great Barrier Reef, which represents the largest repository from any reef system around the globe. This paper presents results from an inventory review of the current collection. The review highlighted the skew toward five Acropora species and the necessity to increase the taxonomic diversity of the collection. It also highlighted the need to increase geographic representation, even for the most well represented species. The inventory data will inform Taronga’s future research focus and sampling strategy to maximize genetic variation and biodiversity within the biobank and provide a test case for other practitioners implementing biobanking strategies for coral conservation around the world. Through co-investment and collaboration with research partners over the next decade, Taronga will prioritize and resource critical applied research and expand biobanking efforts to assist interventions for reef recovery and restoration.</p