Design sequence

GLP-1R

The receptor behind the GLP-1 drugs, whose molecules were aimed at what happens to the whole body rather than at the receptor itself.

01 · Proteome

Signal spreads across a map of how human proteins interact.All natural human proteins

A six-part sequence built from real computational objects. It begins with Synthyra’s predicted human protein-interaction map of 19,982 reviewed proteins, in which a signal propagates along predicted edges. The map resolves to a single protein, the glucagon-like peptide-1 receptor (UniProt P43220, node 5,681), whose experimentally determined extracellular domain from PDB entry 3IOL is shown as a space-filling molecular surface moving along its elastic-network normal modes, with the GLP-1 peptide agonist in its crystallographic pose. The sequence then adds a SwissBioPics human-cell diagram carrying the same network placed by curated UniProt subcellular-location annotation, a rail of six marketed oral antidiabetics linked to the proteins they are predicted to bind, and Human-GEM version 2.0.0, a published genome-scale metabolic model of 12,931 reactions and 8,461 metabolites, drawn as a metabolite-by-reaction incidence map. One candidate column and nine constraint rows are added while the published model is held fixed. A single candidate binder is then refined across four design passes, jointly constrained by the interaction map and the metabolic model, while the readouts update.

Info

Where every object on screen came from.

Interaction map: Synthyra Atlas-PPI predicted human interactome, 19,982 reviewed proteins.
Cell diagram: SwissBioPics animal cell, SIB Swiss Institute of Bioinformatics, CC BY 4.0. Redrawn as line art.
Protein structure: PDB 3IOL chain A, residues 29 to 128: the GLP-1R extracellular domain. Public domain (CC0). Underwood et al., J Biol Chem, 2010.
Motion: Anisotropic network model normal modes over C-alpha atoms within 13 angstrom, first six non-trivial modes.
Metabolic model: Human-GEM v2.0.0, SysBioChalmers, CC BY 4.0. Ten central-metabolism subsystems shown, currency metabolites hidden.
Co-prescribed compounds: Empagliflozin, dapagliflozin, linagliptin, glimepiride, repaglinide and glyburide, from the Atlas protein-ligand screen.
Ontology terms: Glucagon receptor activity (GO:0004967, 2 proteins), G protein-coupled peptide receptor activity (GO:0008528, 20), activation of adenylate cyclase activity (GO:0007190, 10).
Pathway and disease identifiers: Reactome R-HSA-381676, GLP-1 regulates insulin secretion. MONDO:0005148, type 2 diabetes mellitus, is the modeling context.

Nothing in this sequence is an illustration. Each readout is a prediction, and it shows direction rather than an absolute number. What each object is and where it came from is in the disclosure above.