4amz

PROLYL OLIGOPEPTIDASE FROM PORCINE BRAIN WITH A COVALENTLY BOUND INHIBITOR IC-2

spinqualitylabelsall models 4amz, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4amz is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 2P4, GOL Related: 1e5t, 1e8m, 1e8n, 1h2w, 1h2x, 1h2y, 1h2z, 1o6f, 1o6g, 1qfm, 1qfs, 1uoo, 1uop, 1uoq, 1vz2, 1vz3, 2xdw, 4amy, 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 Altered prolyl oligopeptidase (PREP) activity is found in many common neurological and other genetic disorders, and in some cases PREP inhibition may be a promising treatment. The active site of PREP resides in an internal cavity; in addition to the direct interaction between active site and substrate or inhibitor, the pathway to reach the active site (the gating mechanism) must be understood for more rational inhibitor design and understanding PREP function. The gating mechanism of PREP has been investigated through molecular dynamics (MD) simulation combined with crystallographic and mutagenesis studies. The MD results indicate the inter-domain loop structure, comprised of 3 loops at residues, 189-209 (loop A), 577-608 (loop B), and 636-646 (loop C) (porcine PREP numbering), are important components of the gating mechanism. The results from enzyme kinetics of PREP variants also support this hypothesis: When loop A is (1) locked to loop B through a disulphide bridge, all enzyme activity is halted, (2) nicked, enzyme activity is increased, and (3) removed, enzyme activity is only reduced. Limited proteolysis study also supports the hypothesis of a loop A driven gating mechanism. The MD results show a stable network of H-bonds that hold the two protein domains together. Crystallographic study indicates that a set of known PREP inhibitors inhabit a common binding conformation, and this H-bond network is not significantly altered. Thus the domain separation, seen to occur in lower taxa, is not involved in the gating mechanism for mammalian PREP. In two of the MD simulations we observed a conformational change that involved the breaking of the H-bond network holding loops A and B together. We also found that this network was more stable when the active site was occupied, thus decreasing the likelihood of this transition. Molecular dynamics, crystallography and mutagenesis studies on the substrate gating mechanism of prolyl oligopeptidase.,Kaszuba K, Rog T, Danne R, Canning P, Fulop V, Juhasz T, Szeltner Z, St Pierre JF, Garcia-Horsman A, Mannisto PT, Karttunen M, Hokkanen J, Bunker A Biochimie. 2012 Jun;94(6):1398-411. Epub 2012 Mar 30. PMID:22484394 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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