4ax4 | pdb_00004ax4

PROLYL OLIGOPEPTIDASE FROM PORCINE BRAIN, H680A MUTANT

spinqualitylabelsall models 4ax4, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ax4 is a 1 chain structure with sequence from Pig. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL Related: 1e5t, 1e8m, 1e8n, 1h2w, 1h2x, 1h2y, 1h2z, 1o6f, 1o6g, 1qfm, 1qfs, 1uoo, 1uop, 1uoq, 1vz2, 1vz3, 2xdw, 4amy, 4amz, 4an0, 4an1 Activity: Prolyl oligopeptidase, with EC number 3.4.21.26 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [PPCE_PIG] Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. Publication Abstract from PubMed Prolyl oligopeptidase (POP) has emerged as a drug target for neurological diseases. A flexible loop structure comprising loop A (res. 189-209) and loop B (res. 577-608) at the domain interface is implicated in substrate entry to the active site. Here we determined kinetic and structural properties of POP with mutations in loop A, loop B, and in two additional flexible loops (the catalytic His loop, propeller Asp/Glu loop). POP lacking loop A proved to be an inefficient enzyme, as did POP with a mutation in loop B (T590C). Both variants displayed an altered substrate preference profile, with reduced ligand binding capacity. Conversely, the T202C mutation increased the flexibility of loop A, enhancing the catalytic efficiency beyond that of the native enzyme. The T590C mutation in loop B increased the preference for shorter peptides, indicating a role in substrate gating. Loop A and the His loop are disordered in the H680A mutant crystal structure, as seen in previous bacterial POP structures, implying coordinated structural dynamics of these loops. Unlike native POP, variants with a malfunctioning loop A were not inhibited by a 17-mer peptide that may bind non-productively to an exosite involving loop A. Biophysical studies suggest a predominantly closed resting state for POP with higher flexibility at the physiological temperature. The flexible loop A, loop B and His loop system at the active site is the main regulator of substrate gating and specificity and represents a new inhibitor target. The loops facing the active site of prolyl oligopeptidase are crucial components in substrate gating and specificity.,Szeltner Z, Juhasz T, Szamosi I, Rea D, Fulop V, Modos K, Juliano L, Polgar L Biochim Biophys Acta. 2012 Aug 19. PMID:22940581 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Prolyl Endopeptidase

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