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TitleTuning insulin receptor signaling using de novo-designed agonists.
Journal, issue, pagesMol Cell, Vol. 85, Issue 21, Page 4064-44081.e9, Year 2025
Publish dateNov 6, 2025
AuthorsXinru Wang / Sarah Cardoso / Kai Cai / Preetham Venkatesh / Albert Hung / Michelle Ng / Catherine Hall / Brian Coventry / David S Lee / Rishabh Chowhan / Stacey Gerben / Jie Li / Weidong An / Mara Hon / Michael Gao / Ya-Cheng Liao / Domenico Accili / Eunhee Choi / Xiao-Chen Bai / David Baker /
PubMed AbstractInsulin binding induces conformational changes in the insulin receptor (IR) that activate the intracellular kinase domain and the protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) ...Insulin binding induces conformational changes in the insulin receptor (IR) that activate the intracellular kinase domain and the protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways, regulating metabolism and proliferation. We reasoned that designed agonists inducing different IR conformational changes might induce different downstream responses. We used de novo protein design to generate binders for individual IR extracellular domains and fused them in different orientations with different conformational flexibility. We obtained a series of synthetic IR agonists that elicit a wide range of receptor autophosphorylation, MAPK activation, trafficking, and proliferation responses. We identified designs more potent than insulin, causing longer-lasting glucose lowering in vivo and retaining activity on disease-causing IR mutants, while largely avoiding the cancer cell proliferation induced by insulin. Our findings shed light on how changes in IR conformation and dynamics translate into downstream signaling, and with further development, our synthetic agonists could have therapeutic utility for metabolic and proliferative diseases.
External linksMol Cell / PubMed:41086805 / PubMed Central
MethodsEM (single particle)
Resolution4.0 - 8.2 Å
Structure data

47031

9dn6

EMDB-47031, PDB-9dn6:
Insulin receptor bound with de novo designed agonist called "RF-405".
Method: EM (single particle) / Resolution: 4.0 Å

47041

9dni

EMDB-47041, PDB-9dni:
Insulin receptor bound with de novo designed agonist called "S2-F1-S1"
Method: EM (single particle) / Resolution: 8.2 Å

47043

9dnn

EMDB-47043, PDB-9dnn:
Insulin receptor in complex with both insulin and de novo designed site-2 binder "S2B".
Method: EM (single particle) / Resolution: 6.1 Å

Source
  • homo sapiens (human)
  • synthetic construct (others)
  • mus musculus (house mouse)
KeywordsSIGNALING PROTEIN / Insulin receptor / de novo designed agonist / insulin / designed binder

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