
ALT A multi‑panel structural map of the RET extracellular domain highlighting residues linked to Hirschsprung’s disease. Panel A shows 43 co‑receptor–interacting residues as purple spheres, with four disease‑associated mutations marked by arrows. Panel B shows 24 ligand‑interacting residues as blue spheres, with one mutated position indicated. Panel C shows 19 calcium‑binding residues as light‑green spheres, with three mutated positions marked. Panel D shows 222 buried core residues as brown spheres, with 36 mutated positions labeled. Panel E highlights 14 residues that stabilize RET structure through hydrogen bonds, salt bridges, or disulfide bonds, shown in shades of pink and olive, with arrows marking disease‑linked mutations. Panel F shows six positions involving proline or glycine substitutions that destabilize the structure, displayed as teal spheres with arrows.

ALT RESEARCH ARTICLE Simulating 500 million years of evolution with a language model. Figure 1E, shown here, displays unconditional generations from ESM3 98B (colored by sequence identity to the nearest sequence in the training set), embedded by ESM3, and projected by UMAP alongside randomly sampled sequences from UniProt (in gray). Generations are diverse, high quality, and cover the distribution of natural sequences.























