9d9c

Incorporation of dehydro-aza-proline residues in avian pancreatic polypeptide: Aza-Pro substitution at positions 4 and 6

spinqualitylabelsall models 9d9c Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9d9c is a 2 chain structure with sequence from Meleagris gallopavo. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR, 10 models Ligands: A1A3M, NH2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PAHO_MELGA Pancreatic hormone is synthesized in pancreatic islets of Langerhans and acts as a regulator of pancreatic and gastrointestinal functions. Publication Abstract from PubMed The unique role of proline in modulating protein folding and recognition makes it an attractive target for substitution to generate new proteomimetics. The design, synthesis, and conformational analysis of non-canonical surrogates can also aid in parsing the role of prolyl stereoelectronic effects on structure. We recently described the synthesis and conformational analysis of dehydro-delta-azaproline (DeltaaPro), a novel unsaturated analogue of proline featuring a planar dehydropyrazine ring. When incorporated into host sequences, this backbone N-aminated proline surrogate forms an acylhydrazone bond with an unusually high trans rotamer bias and low isomerization barrier. Here, we used CD, NMR spectroscopy, and MD simulations to evaluate the impact of DeltaaPro substitution within the polyproline II (PPII) and loop regions of the avian pancreatic polypeptide (aPP). The DeltaaPro residue strongly favors PPII conformation and stabilizes the aPP tertiary fold when incorporated at select positions within the miniprotein. A variant featuring three DeltaaPro substitutions was found to significantly enhance the thermal stability of wild-type aPP despite compromising protein dimerization. Our results suggest that the stability of proline-rich folds relies more on backbone torsional preferences than ring puckering and informs strategies for the incorporation of DeltaaPro into thermally stable and functional proteomimetics. Stabilization of a miniprotein fold by an unpuckered proline surrogate.,Wright MM, Rajewski BH, Gerrein TA, Xu Z, Smith LJ, Seth Horne W, Del Valle JR Commun Chem. 2025 Mar 12;8(1):76. doi: 10.1038/s42004-025-01474-6. PMID:40075167 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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