7uxn | pdb_00007uxn

Structure of PPIA in complex with FP29103, a Helicon Polypeptide

spinqualitylabelsall models 7uxn, resolution 1.36Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7uxn is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.36Å Ligands: ACE, WHL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PPIA_HUMAN PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Publication Abstract from PubMed The alpha-helix is one of the most common protein surface recognition motifs found in nature, and its unique amide-cloaking properties also enable alpha-helical polypeptide motifs to exist in membranes. Together, these properties have inspired the development of alpha-helically constrained (Helicon) therapeutics that can enter cells and bind targets that have been considered "undruggable", such as protein-protein interactions. To date, no general method for discovering alpha-helical binders to proteins has been reported, limiting Helicon drug discovery to only those proteins with previously characterized alpha-helix recognition sites, and restricting the starting chemical matter to those known alpha-helical binders. Here, we report a general and rapid screening method to empirically map the alpha-helix binding sites on a broad range of target proteins in parallel using large, unbiased Helicon phage display libraries and next-generation sequencing. We apply this method to screen six structurally diverse protein domains, only one of which had been previously reported to bind isolated alpha-helical peptides, discovering 20 families that collectively comprise several hundred individual Helicons. Analysis of 14 X-ray cocrystal structures reveals at least nine distinct alpha-helix recognition sites across these six proteins, and biochemical and biophysical studies show that these Helicons can block protein-protein interactions, inhibit enzymatic activity, induce conformational rearrangements, and cause protein dimerization. We anticipate that this method will prove broadly useful for the study of protein recognition and for the development of both biochemical tools and therapeutics for traditionally challenging protein targets. De novo mapping of alpha-helix recognition sites on protein surfaces using unbiased libraries.,Li K, Tokareva OS, Thomson TM, Wahl SCT, Travaline TL, Ramirez JD, Choudary SK, Agarwal S, Walkup WG 4th, Olsen TJ, Brennan MJ, Verdine GL, McGee JH Proc Natl Acad Sci U S A. 2022 Dec 27;119(52):e2210435119. doi: , 10.1073/pnas.2210435119. Epub 2022 Dec 19. PMID:36534810 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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