Summary of Gabe Lander - Dana-Farber Targeted Degradation Webinar Series

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In the video, Gabe Lander discusses his work on targeted protein degradation in cells. He explains how cryotherapy can improve the efficacy of drugs used to treat cell mods, and talks about a new drug that was found to be effective in treating a refractory patient population.

  • 00:00:00 This 1-paragraph summary is about a video titled "Gabe Lander - Dana-Farber Targeted Degradation Webinar Series" which discusses how Gabe Lander uses cryo-electrical microscopy to study molecular glues. Cryoelectric microscopy allows for structures at near atomic resolution, which is helpful for confirming variable structures in cells.
  • 00:05:00 The video discusses Gabe Lander's work with the conformational rearrangements that are associated with biological function. Cryoelectron microscopy has helped to explore the variability and distinct States of the 26s protease and how those States might relate to mechanisms of targeted protein degradation. Gabe Lander also describes the work of his group with the adapter protein ddb1, which has been involved in more than just DNA repair.
  • 00:10:00 This video covers the basics of theadaptive protein ubiquitination system, including the Groove binding pocket and its various substrates. Recent work has identified a ligand for the dw1 cerebellum co-complex, thalidomide, which binds in this pocket. This information is important for understanding how these ligands interact with the target protein and offers potential new therapies for several cancers.
  • 00:15:00 In this video, Gabe Lander from the Celgene research team discusses how they discovered that the thalidomide analog Cerebellum degradation webinar series interacts with a protein in the cerebral cerebellum, leading to the development of new drugs to treat cancer. Lander also discusses the importance of using high resolution electron microscopy to study the conformational variability of the proteins involved.
  • 00:20:00 The video discusses Gabe Lander's work on a Dana-Farber Targeted Degradation webinar series, in which he discusses the crystal structure of Sarah blonde, a protein that binds thalidomide. His team was able to solve the structure before Dana-Farber's team, and found that the protein domains are separated from one another. This allowed them to have some confidence that the confirmation of this open form exists and is not an artifact of negative stain. There was some discussion about pH being a possible cause of the open form, but crystallography has now also seen it.
  • 00:25:00 Gabe Lander, a postdoc at Dana-Farber Cancer Institute, discusses how the degradation of proteins affects electron microscopy results. He explains that although a lower-end microscope is sufficient for the work, the lack of information gained from the structure limits its usefulness. Randy Watson, a postdoc at St. Jude's Children's Research Hospital, worked with Lander on the study.
  • 00:30:00 The video briefly describes Gabe Lander's work on preserving Dw1 Sarah Blonde samples for cryoelectric microscopy. Gabe explains that they use a manual plunging system in the cold room to freeze grids quickly, and then use a mutant icarose construct to prevent the cerebellan complex from binding to cerebralon. They then use blocking techniques to visualize the cerebellan in the open and closed states. Pomalidomide does not seem to promote the transition, suggesting there may be additional factors involved.
  • 00:35:00 The video discusses the findings of a study in which it was found that only 20 out of 100 particles in a complex of pomalidomide and palmolionide are able to form closure, suggesting that additional interactions are necessary for substrate binding. It is hypothesized that the sensor Loop plays a role in this process.
  • 00:40:00 This video discusses the findings of a study investigating the mechanism of action of two drugs, polymalidomide and albertamide, in the treatment of cerebellar degeneration. The study found that both drugs promote the closure of the sensor loop, which is necessary for binding to the substrate and the effective action of the drugs.
  • 00:45:00 In this video, Gabe Lander discusses the importance of using cryotherapy to improve the efficacy of drugs used to treat cell mods such as cancer. He also talks about a refractory patient population that does not respond to traditional therapies. Mesignomide, a new drug discovered by BMS, was found to be effective in treating this population.
  • 00:50:00 Gabe Lander, a biologist at Dana-Farber Cancer Institute, discusses a project to target degradation in cells. His former colleagues at Bristol-Myers Squibb and at Scripps Florida helped start the project, and he thanks them all. He also thanks Ingrid Works, who took over the project after his colleagues left, and Jimmy Novik and Pat Griffin, who collaborated on the HD XMS study.

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