GLP-1 Receptor + Semaglutide — Interactive Structure

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Representation

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Mechanism & half-life human PK · in vitro

Semaglutide is a GLP-1 analogue engineered for once-weekly dosing through three changes to native GLP-1(7–37). Aib at position 8 (replacing Ala) blocks cleavage by DPP-4, the protease that gives native GLP-1 its ~2 min half-life. Lys26 is acylated with a C18 fatty di-acid via a γGlu + 2×OEG spacer; this chain binds serum albumin, slowing renal clearance. Arg34 replaces Lys34 so acylation is directed to the single Lys26. Together these give an albumin-tethered agonist with a half-life of ~1 week (~160 h), while it still engages the GLP-1R orthosteric pocket to drive Gs → cAMP signalling.

Source: Lau J, et al. Discovery of the Once-Weekly GLP-1 Analogue Semaglutide. J Med Chem 2015;58:7370–80. PMID 26308095 · Structure: PDB 7KI0.
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Legend

GLP-1 receptor (7TM + ECD)
Semaglutide peptide backbone
Highlighted residue / linker
C18 di-acid + linker (WF1)