19. Tong M, Ding Y, Tai HH (2006) Histone deacetylase inhibitors and transforming growth factor-beta induce 15-hydroxyprostaglandin dehydroge- nase expression in human lung adenocarcinoma cells. Biochem Pharmacol 72: 701–709. 20. Nishino N, Powers JC (1978) Peptide hydroxamic acids as inhibitors of thermolysin. Biochemistry 17: 2846–2850. 21. Powers JC, Odake S, Oleksyszyn J, Hori H, Ueda T, et al. (1993) Proteases— structures, mechanism and inhibitors. Agents Actions Suppl 42: 3–18. 22. Turk BE, Huang LL, Piro ET, Cantley LC (2001) Determination of protease cleavage site motifs using mixture-based oriented peptide libraries. Nat Biotechnol 19: 661–667. 23. Cabrol C, Huzarska MA, Dinolfo C, Rodriguez MC, Reinstatler L, et al. (2009) Small-molecule activators of insulin-degrading enzyme discovered through high- throughput compound screening. PLoS ONE 4: e5274. 24. Zhao J, Li L, Leissring MA (2009) Insulin-degrading enzyme is exported via an unconventional protein secretion pathway. Mol Neurodegener 4: 4. 25. Duckworth WC (1988) Insulin degradation: mechanisms, products, and significance. Endocr Rev 9: 319–345. 26. Authier F, Metioui M, Fabrega S, Kouach M, Briand G (2002) Endosomal proteolysis of internalized insulin at the C-terminal region of the B chain by cathepsin D. J Biol Chem 277: 9437–9446. 27. Hamel FG, Mahoney MJ, Duckworth WC (1991) Degradation of intraendo- somal insulin by insulin-degrading enzyme without acidification. Diabetes 40: 436–443. 28. Hentz NG, Richardson JM, Sportsman JR, Daijo J, Sittampalam GS (1997) Synthesis and characterization of insulin-fluorescein derivatives for bioanalytical applications. Anal Chem 69: 4994–5000. 29. Terris S, Steiner DF (1975) Binding and degradation of 125I-insulin by rat hepatocytes. J Biol Chem 250: 8389–8398. 30. Song ES, Juliano MA, Juliano L, Fried MG, Wagner SL, et al. (2004) ATP effects on insulin-degrading enzyme are mediated primarily through its triphosphate moiety. J Biol Chem 279: 54216–54220. 31. Im H, Manolopoulou M, Malito E, Shen Y, Zhao J, et al. (2007) Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE. J Biol Chem 282: 25453–25463. 32. Safavi A, Miller BC, Cottam L, Hersh LB (1996) Identification of gamma- endorphin-generating enzyme as insulin-degrading enzyme. Biochemistry 35: 14318–14325. 33. Farris W, Leissring MA, Hemming ML, Chang AY, Selkoe DJ (2005) Alternative splicing of human insulin-degrading enzyme yields a novel isoform with a decreased ability to degrade insulin and amyloid beta-protein. Biochemistry 44: 6513–6525. 34. Song ES, Rodgers DW, Hersh LB (2010) A monomeric variant of insulin degrading enzyme (IDE) loses its regulatory properties. PLoS One 5: e9719. Inhibitors of IDE 35. Song ES, Juliano MA, Juliano L, Hersh LB (2003) Substrate activation of insulin-degrading enzyme (insulysin). A potential target for drug development. J Biol Chem 278: 49789–49794. 36. Watanabe T, Kato H, Kobayashi Y, Yamasaki S, Morita-Hoshi Y, et al. (2009) Potential efficacy of the oral histone deacetylase inhibitor vorinostat in a phase I trial in follicular and mantle cell lymphoma. Cancer Sci. 37. Nuti E, Tuccinardi T, Rossello A (2007) Matrix metalloproteinase inhibitors: new challenges in the era of post broad-spectrum inhibitors. Curr Pharm Des 13: 2087–2100. 38. Mirsky IA (1956) The role of insulinase and insulinase-inhibitors. Metabolism 5: 138–143. 39. Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, et al. (2008) Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 70: 440–448. 40. Garcia JV, Fenton BW, Rosner MR (1988) Isolation and characterization of an insulin-degrading enzyme from Drosophila melanogaster. Biochemistry 27: 4237–4244. 41. Becker AB, Roth RA (1995) Insulysin and pitrilysin: insulin-degrading enzymes of mammals and bacteria. Methods Enzymol 248: 693–703. 42. Malito E, Ralat LA, Manolopoulou M, Tsay JL, Wadlington NL, et al. (2008) Molecular bases for the recognition of short peptide substrates and cysteine- directed modifications of human insulin-degrading enzyme. Biochemistry 47: 12822–12834. 43. Otwinowski Z, Minor W (1997) Processing of X-ray diffraction data collected in oscillation mode. Methods in Enzymology 276(Macromolecular Crystallogra- phy, Part A). pp 307–326. 44. McCoy A, Grosse-Kunstleve R, Adams P, Winn M, Storoni L, et al. (2007) Phaser crystallographic software. J Appl Crystallogr 40: 658–674. 45. Adams PD, Grosse-Kunstleve RW, Hung LW, Ioerger TR, McCoy AJ, et al. (2002) PHENIX: building new software for automated crystallographic structure determination. Acta Crystallogr D 58: 1948–1954. 46. Emsley P, Cowtan K (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60: 2126–2132. 47. Brunger AT, Adams PD, Clore GM, DeLano WL, Gros P, et al. (1998) Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr 54: 905– 921. 48. Farris W, Mansourian S, Leissring MA, Eckman EA, Bertram L, et al. (2004) Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am J Pathol 164: 1425–1434. 49. Seta KA, Roth RA (1997) Overexpression of insulin-degrading enzyme: cellular localization and effects on insulin signaling. Biochem Biophys Res Commun 231: 167–171. 50. DeLano WL (2002) The PyMOL Molecular Graphics System. Palo Alto CA: DeLano Scientific. PLoS ONE | www.plosone.org 13 May 2010 | Volume 5 | Issue 5 | e10504