7ube | pdb_00007ube

Solution NMR structure of 8-residue Rosetta-designed cyclic peptide D8.21 in d6-DMSO with cis/trans switching

spinqualitylabelsall models 7ube Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ube is a 1 chain structure with sequence from Synthetic construct. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: DPR, DVA, MLE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed We use computational design coupled with experimental characterization to systematically investigate the design principles for macrocycle membrane permeability and oral bioavailability. We designed 184 6-12 residue macrocycles with a wide range of predicted structures containing noncanonical backbone modifications and experimentally determined structures of 35; 29 are very close to the computational models. With such control, we show that membrane permeability can be systematically achieved by ensuring all amide (NH) groups are engaged in internal hydrogen bonding interactions. 84 designs over the 6-12 residue size range cross membranes with an apparent permeability greater than 1 x 10(-6) cm/s. Designs with exposed NH groups can be made membrane permeable through the design of an alternative isoenergetic fully hydrogen-bonded state favored in the lipid membrane. The ability to robustly design membrane-permeable and orally bioavailable peptides with high structural accuracy should contribute to the next generation of designed macrocycle therapeutics. Accurate de novo design of membrane-traversing macrocycles.,Bhardwaj G, O'Connor J, Rettie S, Huang YH, Ramelot TA, Mulligan VK, Alpkilic GG, Palmer J, Bera AK, Bick MJ, Di Piazza M, Li X, Hosseinzadeh P, Craven TW, Tejero R, Lauko A, Choi R, Glynn C, Dong L, Griffin R, van Voorhis WC, Rodriguez J, Stewart L, Montelione GT, Craik D, Baker D Cell. 2022 Aug 25. pii: S0092-8674(22)00922-9. doi: 10.1016/j.cell.2022.07.019. PMID:36041435 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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