Study maps how tirzepatide grips its two hormone receptors

Scientists have published detailed 3D images of tirzepatide — the molecule sold in the United States as Mounjaro and Zepbound — attached to the two hormone receptors it activates, along with images of a three-target experimental peptide. The structures appeared in a study in Nature Communications in February 2022 ^[1].

Tirzepatide is a once-weekly drug that switches on two receptors at the same time: GIPR (the receptor for glucose-dependent insulinotropic polypeptide) and GLP-1R (the receptor for glucagon-like peptide-1) ^[1]. The researchers also imaged peptide 20, an experimental compound designed to hit three receptors: GIPR, GLP-1R and GCGR, the glucagon receptor ^[1]. Five structures were determined, and all of them include the signaling protein Gs ^[1]. The paper describes the resulting view of how the drugs interact with their targets as showing key interactions of clinical relevance at the near-atomic level ^[1].

The tirzepatide-bound GIPR complex has been deposited in the Protein Data Bank under the accession code 7FIY, with an associated electron microscopy map, EMD-31606 ^[2].

GIP, GLP-1 and glucagon are peptide hormones involved in controlling blood sugar, and their receptors belong to the same family of proteins ^[1]. The paper notes a complication that has made GIP- and glucagon-based drugs hard to develop: GIP stimulates insulin release but also raises glucagon levels, and glucagon in turn raises both energy expenditure and blood glucose ^[1]. The authors report that keeping glucagon activity is what allows a multi-receptor drug to outperform therapy that targets GLP-1 alone ^[1].

At the time of publication, tirzepatide was described as an investigational once-weekly GIPR/GLP-1R dual agonist ^[1]. The authors point to head-to-head clinical trials in which it reduced blood glucose and body weight by more than the approved drugs semaglutide and dulaglutide ^[1]. Semaglutide is the molecule sold as Ozempic, Wegovy and Rybelsus. Peptide 20, also known as MAR423, is a GIPR/GLP-1R/GCGR triagonist with balanced potency at the three receptors, and its phase 1 trials had been completed ^[1]. The paper counts more than a dozen multi-targeting peptides that had entered clinical development: two GIPR/GLP-1R dual agonists, ten GLP-1R/GCGR dual agonists and five GIPR/GLP-1R/GCGR triagonists ^[1].

The study also notes that the weight-loss effect of most GLP-1 analogs is limited by dose-dependent side effects, and describes once-weekly subcutaneous semaglutide as an exception because its behavior in the body is smoother ^[1].

Why it matters for patients

This is laboratory structural biology. The receptors were studied in purified form, not in people, and the paper reports no patient outcomes, no doses and no side-effect rates ^[1]. It does not show that tirzepatide or peptide 20 works better, or is safer, for any individual.

What it does offer is a physical explanation for a difference patients already encounter in the clinic. Tirzepatide is built to engage two receptors, while semaglutide is described in the paper as a monoagonist that engages one ^[1]. Peptide 20, which is not an approved medicine, is built to engage three, including glucagon — a receptor that raises blood sugar at the same time it raises energy use ^[1]. That design tension is the reason the authors say glucagon activity has to be retained, not removed, for the triple approach to beat GLP-1-only treatment ^[1].

How the structures translate into weight lost or blood sugar lowered in real patients has not been reported.

What happens next

The paper does not give dates for later-phase trials of peptide 20; at publication, only its phase 1 studies were described as completed, and no phase 2 or phase 3 results appear in the study ^[1]. Tirzepatide was still described as investigational ^[1], and the study does not address its regulatory status in the United States. Whether these structural findings lead to modified or new multi-receptor drugs has not been disclosed.