Design sequence

PD-1

The receptor behind Keytruda and Opdivo, traced from a map of every human protein into a model of how the whole cell runs.

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 Synthyraâ€™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, PD-1 (gene PDCD1, UniProt Q15116, node 8,233), whose experimentally determined structure from PDB entry 5B8C is shown as a space-filling molecular surface moving along its elastic-network normal modes. The sequence then adds a SwissBioPics human-cell diagram carrying the same network placed by curated UniProt subcellular-location annotation, a rail of marketed compounds 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 modeled target engagement, pathway response, off-target breadth, liability proxies and ligand overlap update, before the bound complex settles at the centre of the frame. All outcomes shown are model predictions.

Sources and licenses

Every object below is a real computational artifact. Readouts are modeled.

Interaction map: Synthyra Atlas-PPI predicted human interactome, 19,982 reviewed proteins. Edges are model predictions.
Cell diagram: SwissBioPics animal cell, SIB Swiss Institute of Bioinformatics, CC BY 4.0. Redrawn as single-weight line art, embedded logos removed.
Protein structure: PDB 5B8C chain C, the PD-1 ectodomain. Public domain (CC0). Horita et al., Scientific Reports, 2016.
Motion: Anisotropic elastic-network normal modes from the C-alpha positions of 5B8C chain C.
Metabolic model: Human-GEM v2.0.0, SysBioChalmers, CC BY 4.0. Ten central-metabolism subsystems shown, currency metabolites hidden, rows and columns reordered. No reaction added or removed.
Compounds: Co-administered with pembrolizumab in registrational trials: pemetrexed (KEYNOTE-189), paclitaxel (KEYNOTE-407), gemcitabine (KEYNOTE-355), axitinib (KEYNOTE-426), fluorouracil (KEYNOTE-590), olaparib (KEYLYNK-010). Predicted targets from the Atlas protein-ligand screen.
Ontology terms: MHC protein binding (GO:0042287, 9 proteins), T cell receptor complex (GO:0042101, 53), adaptive immune response (GO:0002250, 420).
Pathway and disease identifiers: Reactome R-HSA-389948, PD-1 signaling. MONDO:0005105, melanoma, is the modeling context.

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