Thank you, Neel!

Collaboration with John Wad (Melbourne), Marc Tatar (Brown), & Xiaochen Bai (UTSW). Congratulations Michelle and Kai!

We discovered that different insulin-like peptides induce distinct active conformations of the same receptor, tuning signaling strength and physiological outcomes.
Nature’s clever design — many signals, one receptor. 🌿

Humans have three IR-family receptors (IR, IGF1R, and IRR) — structurally similar, yet functionally distinct.
Flies, however, have just one receptor activated by multiple insulin-like peptides, making them a powerful system to decode how ligand diversity drives receptor function.

Humans have three IR-family receptors (IR, IGF1R, and IRR) — structurally similar, yet functionally distinct.
Flies, however, have just one receptor activated by multiple insulin-like peptides, making them a powerful system to decode how ligand diversity drives receptor function.

Proud collaboration with the Baker Lab (UW) and Bai Lab (UTSW).
#ProteinDesign #InsulinReceptor #MolecularCell #BiasedAgonism #TranslationalScience

Mechanistically, these ligands reveal how different IR conformations drive distinct signaling outcomes — offering both mechanistic insight and potential therapies for diabetes, cancer, and severe insulin resistance syndromes.

⚙️ Balanced agonists mimic insulin’s full activity on metabolism and growth.
⚖️ Partial/biased agonists activate only the metabolic branch, without triggering receptor endocytosis or proliferation.
🚫 Antagonists block insulin-dependent activation.

Using computational protein design, we developed de novo ligands that induce distinct active conformations of the insulin receptor (IR) — including balanced agonists, partial/biased agonists, and antagonists.

Thank you for your great comments for this Review!