Invitation Only
Speaker: Daryl Klein, MD, Ph.D., Yale School of Medicine
Title: Mechanisms to Medicines: Structural Blueprints for Targeting Receptor Signaling
Cell-surface receptors are often interpreted through canonical models in which ligand binding, receptor clustering, or channel opening provides a direct route to signaling output or ion flux. Work from the Klein lab reveals a more nuanced and therapeutically exploitable logic: clustering alone may be insufficient for activation, excess agonist can become inhibitory, and ion channels can be retooled as noncanonical signaling platforms. Using structural biology, biochemistry, cell signaling, and antibody discovery, the we define how extracellular receptor architecture encodes regulatory states that can be redirected for therapeutic design. Studies of GABAA receptor π/GABRP suggest that this receptor has evolved away from conventional chloride channel function toward asymmetric, G protein-dependent signaling that can be blocked by antibodies. Parallel work on ROS1 demonstrates that ligand-induced clustering must be coupled to an extracellular conformational switch to drive receptor activation, establishing a structural framework for rational biologic targeting. Emerging studies of ErbB receptors further reveal how ligand occupancy and inactive receptor assemblies can shape signaling output in unexpected ways. Together, these systems illustrate how decoding receptor regulation at molecular resolution can uncover hidden vulnerabilities and provide structural blueprints for next-generation therapeutics.