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. 2017 May 26;7:2456. doi: 10.1038/s41598-017-02550-1

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© The Author(s) 2017

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Structure of PREP and current models for the substrate gating and molecular function mechanisms. (A) PREP structure and domain organization (PDB accession entry: 1H2W) in a front (left) and back (right) view. Human PREP and its homologues are two-domain assemblies consisting of an α/β hydrolase domain (light grey) and a 7-bladed β-propeller (dark grey). (B) The two domains are connected through a two-linker hinge (purple). Hinge _out connects the N-terminal segment of the α/β hydrolase domain with the first β-propeller β-strand. Hinge _in links the last β-propeller strand with the rest α/β hydrolase domain. The catalytic triad in the α/β hydrolase domain comprises of the His680 residue from the His-loop (residues 676–685), Asp641 from loop C (636–646) and Ser554 (right; zoom in view of the active site and its surrounding loops; catalytic triad in blue; loops in red). PREP substrates and its hydrolase inhibitors bind to the active site (PDB accession entry 4AN0; inhibitor KYP-2047 shown as pink spheres). Loops A (189–209) and B (577–608) (red) surround the active site. The propeller-like configuration of the β-blades in the β-propeller domain create a ~4Å-wide pore. The blade unit is 4 antiparallel β-strands. (C–F) Current models for the substrate gating mechanism of PREP. A hypothetical substrate/inhibitor is drawn as a pink line; dash-lined arrows represent motions of PREP regions related to gating; continuous-lined arrows indicate the suggested substrate entry pathway. (C) Loop A (red) has been suggested to move outwards enabling side entry of PREP substrates (PDB accession entry: 1H2W; loop A was manually translated outwards using PyMOL Molecular Graphics System, Version 1.8 Schrödinger, LLC). (D) The β-propeller pore may dilate for substrate encapsulation, while loop A outward motions may provide the exit pathway (structure as in panel C). (E) Bilateral opening of the inter-domain interface by large scale outward motions of both domains around the hinge would expose the active site (PDB accession entry: 4BP8; Trypanosoma brucei Prolyl Oligopeptidase B). (F) The unclosed β-propeller between blades 1 and 7 may provide a side tunnel by weakening interactions between the two β-stranded blades (bottom view of the β-propeller; structure as in panel A).