8gji | pdb_00008gji
De novo design of high-affinity protein binders to bioactive helical peptides
Structural highlights
FunctionGLUC_MESAU Plays a key role in glucose metabolism and homeostasis. Regulates blood glucose by increasing gluconeogenesis and decreasing glycolysis. A counterregulatory hormone of insulin, raises plasma glucose levels in response to insulin-induced hypoglycemia. Plays an important role in initiating and maintaining hyperglycemic conditions in diabetes.[UniProtKB:P55095] Potent stimulator of glucose-dependent insulin release. Also stimulates insulin release in response to IL6. Plays important roles on gastric motility and the suppression of plasma glucagon levels. May be involved in the suppression of satiety and stimulation of glucose disposal in peripheral tissues, independent of the actions of insulin. Has growth-promoting activities on intestinal epithelium. May also regulate the hypothalamic pituitary axis (HPA) via effects on LH, TSH, CRH, oxytocin, and vasopressin secretion. Increases islet mass through stimulation of islet neogenesis and pancreatic beta cell proliferation. Inhibits beta cell apoptosis.[UniProtKB:P55095] Stimulates intestinal growth and up-regulates villus height in the small intestine, concomitant with increased crypt cell proliferation and decreased enterocyte apoptosis. The gastrointestinal tract, from the stomach to the colon is the principal target for GLP-2 action. Plays a key role in nutrient homeostasis, enhancing nutrient assimilation through enhanced gastrointestinal function, as well as increasing nutrient disposal. Stimulates intestinal glucose transport and decreases mucosal permeability.[UniProtKB:P55095] Significantly reduces food intake. Inhibits gastric emptying in humans. Suppression of gastric emptying may lead to increased gastric distension, which may contribute to satiety by causing a sensation of fullness.[UniProtKB:P55095] May modulate gastric acid secretion and the gastro-pyloro-duodenal activity. May play an important role in intestinal mucosal growth in the early period of life.[UniProtKB:P55095] Publication Abstract from PubMedMany peptide hormones form an alpha-helix upon binding their receptors(1-4), and sensitive detection methods for them could contribute to better clinical management of disease(5). De novo protein design can now generate binders with high affinity and specificity to structured proteins(6,7). However, the design of interactions between proteins and short peptides with helical propensity is an unmet challenge. Here, we describe parametric generation and deep learning-based methods for designing proteins to address this challenge. We show that by extending RFdiffusion(8) to enable binder design to flexible targets, and to refining input structure models by successive noising and denoising (partial diffusion), picomolar affinity binders can be generated to helical peptide targets both by refining designs generated with other methods, or completely de novo starting from random noise distributions. To our knowledge these are the highest affinity designed binding proteins against any protein or small molecule target generated directly by computation without any experimental optimisation. The RFdiffusion designs enable the enrichment and subsequent detection of parathyroid hormone and glucagon by mass spectrometry, and the construction of bioluminescence-based protein biosensors. The ability to design binders to conformationally variable targets, and to optimise by partial diffusion both natural and designed proteins, should be broadly useful. De novo design of high-affinity binders of bioactive helical peptides.,Torres SV, Leung PJY, Venkatesh P, Lutz ID, Hink F, Huynh HH, Becker J, Yeh AH, Juergens D, Bennett NR, Hoofnagle AN, Huang E, MacCoss MJ, Exposit M, Lee GR, Bera AK, Kang A, De La Cruz J, Levine PM, Li X, Lamb M, Gerben SR, Murray A, Heine P, Korkmaz EN, Nivala J, Stewart L, Watson JL, Rogers JM, Baker D Nature. 2023 Dec 18. doi: 10.1038/s41586-023-06953-1. PMID:38109936[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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