5vid | pdb_00005vid
Receptor binding domain of BoNT/B in complex with mini-protein binder Bot.0671.2
Structural highlights
Function[BXB_CLOBO] Botulinum toxin acts by inhibiting neurotransmitter release. It binds to peripheral neuronal synapses, is internalized and moves by retrograde transport up the axon into the spinal cord where it can move between postsynaptic and presynaptic neurons. It inhibits neurotransmitter release by acting as a zinc endopeptidase that cleaves the '76-Gln-|-Phe-77' bond of synaptobrevin-2. Publication Abstract from PubMedDe novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing. Massively parallel de novo protein design for targeted therapeutics.,Chevalier A, Silva DA, Rocklin GJ, Hicks DR, Vergara R, Murapa P, Bernard SM, Zhang L, Lam KH, Yao G, Bahl CD, Miyashita SI, Goreshnik I, Fuller JT, Koday MT, Jenkins CM, Colvin T, Carter L, Bohn A, Bryan CM, Fernandez-Velasco DA, Stewart L, Dong M, Huang X, Jin R, Wilson IA, Fuller DH, Baker D Nature. 2017 Oct 5;550(7674):74-79. doi: 10.1038/nature23912. Epub 2017 Sep 27. PMID:28953867[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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