Rules of engagement: How G3BP2 paves the way to rationalize novel degrons

Molecular glue degraders (MGDs) are small-molecule compounds that divert E3 ligases to degrade nonnatural substrates called neosubstrates. Clinically effective MGDs bind cereblon (CRBN), a substrate receptor of the Cullin 4–RING E3 ubiquitin ligase (CRL4^CRBN), and recruit neosubstrates to an MGD-induced neosurface on the CRBN CULT domain through molecular mimicry of a natural CRBN degron. Here, we identify G3BP2 (Ras–GAP SH3 domain-binding protein 2), a neosubstrate that bypasses canonical interactions with CRBN by engaging an unconventional binding site on the CRBN LON domain. The ternary complex interface does not resemble known interactions with CRBN. Instead, CRBN leverages a preexisting protein–protein interaction (PPI) hotspot on the target protein by mimicking an endogenous binding partner of G3BP2. Our findings suggest that composite neosurfaces that mimic and stabilize the footprint of natural PPIs (in short, glueprints’) could become a viable strategy for the rational expansion of the MGD target repertoire. In this webinar, we will share the journey of elucidating the G3BP2 binding mode with the CRBN–MGD complex through a multifaceted approach showcasing the capabilities of our QUEEN™ platform - the drug discovery engine at Monte Rosa Therapeutics - including a special focus on our structural biology workflow for cryo-electron microscopy (cryo-EM) structure determination.

We will explore:

Molecular glue degraders (MGDs) as a novel therapeutic approach for challenging drug targets
Integrated approaches of our QUEEN™ platform to enable the rational discovery of novel binding modes
Spotlight on our cryo-EM pipeline: including elucidating ternary complex interfaces, coping with conformational heterogeneity and other examples

First name

Last name

Company

Job Title

Country

State/Province

Which of the following areas of discovery or development are you working in?

Small Molecule Therapeutics

TPD or Molecular Glue Degraders

Antibody Therapeutics

Vaccine Design

Drug Formulation

Other

Would your organization be interested in hearing from an expert in cryo-EM to find out more about its measurable impact on drug discovery pipelines?

No cost to register, subject to confirmation

By registering for this event, you accept that you may receive direct communication from Endpoints News and/or the sponsor(s). View how we use your data here.

If you are experiencing problems with your registration, please try the Zoom registration page.

Georg Petzold

Associate Director of Biology, Monte Rosa Therapeutics

Georg is Associate Director of Biology at Monte Rosa Therapeutics. He received his master’s degree in Biochemistry/Biophysics, Physical Chemistry and Molecular Biology from the University of Heidelberg. He received his Ph.D. in Molecular and Structural Biology studying E3 Ubiquitin Ligases from the Research Institute of Molecular Pathology, University of Vienna. He has been with Monte Rosa Therapeutics since 2021.

Chao Quan

Senior Scientist of Structural Biology, Monte Rosa Therapeutics

Chao is Senior Scientist of Structural Biology at Monte Rosa Therapeutics. He received his master’s degree in Biochemistry and Molecular Biology from The Pennsylvania State University. Chao works on MGD-induced complexes of E3 ligases with neosubstrates using cryo-EM and X-ray crystallography. Prior to joining Monte Rosa Therapeutics, he was a structural biologist at Biogen supporting structure-based design of antibodies and non-antibody biologics.

moderator

Jaime Green

Freelance Journalist & Science Writer

Jaime Green is a freelance science writer and author. Her work has appeared in The New York Times Magazine, The Atlantic, Aeon, Popular Science, Slate, Astrobites, and elsewhere. She is the series editor of The Best American Science and Nature Writing and author of The Possibility of Life: Science, Imagination, and Our Quest for Kinship in the Cosmos.