5. Conclusions
The DP8 model produced was very similar to the DPIV structure in the α/β hydrolase domain. Analysis of the active site of the DP8 model revealed significant structural conservation in the catalytic triad between DPIV, PEP and ACPH. Further analysis is required to determine whether any differences in the substrate pockets or substrate access tunnel(s) may contribute to DP8’s ability to act as a dipeptidyl peptidase, endopeptidase and acylaminoacyl peptidase. As the structure of fibroblast activation protein has recently been published, an alternative model may be made using this structure together with DPIV to make a model based on two enzymatically active proteins. Simulated docking of substrates and inhibitors into the model may uncover subtle differences between the structures. This may aid in determining the reason for DP8’s multiple enzyme functionality and aid in the improvement of DPIV inhibitor specificity.
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References
Abbott, CA and Gorrell, MD (2002) In Ectopeptidases (Langner J and Ansorge S, Eds) Kluwer Academic/Plenum Publishers, New York.
Abbott, CA, Yu, DMT, Woollatt, E, Sutherland, G, McCaughan, GW and Gorrell, MD, 2000, Cloning, expression and chromosomal localization of a novel dipeptidyl peptidase (DPP) IV homolog, DPP8. E J Biochem 267: 6140–6150.
Aertgeerts, K, Levin, I, Shi, L, Snell, GP, Jennings, A, Prasad, GS, Zhang, Y, Kraus, ML, Salakian, S, Sridhar, V, Wijands, R and Tennant, MG, 2005, Structural and Kinetic Analysis of the Substrate Specificity of Human Fibroblast Activation Protein Alpha. J Biol Chem In Press.
Baker, EN, Arcus, VL and Lott, JS, 2003, Protein structure prediction and analysis as a tool for functional genomics. App Bioinf 2: S3–10.
Bartlam, M, Wang, G, Yang, H, Gao, R, Zhao, X, Xie, G, Cao, S, Feng, Y and Rao, Z, 2004, Crystal structure of an acylpeptide hydrolase/esterase from Aeropyrum pernix K1. Structure 12: 1481–8.
Bjelke, JR, Christensen, J, Branner, S, Wagtmann, N, Olsen, C, Kanstrup, AB and Rasmussen, HB, 2004, Tyrosine 547 constitutes an essential part of the catalytic mechanism of dipeptidyl peptidase IV. J Biol Chem 279: 34691–7.
Chen, Y, Chien, C, Goparaju, C, Hsu, J, Liang, P and Chen, X, 2004, Purification and characterization of human prolyl dipeptidyl peptidase DP8 in Sf9 insect cells. Prot Exp Pur 35: 142–146.
Collaborative Computational Project, N, 1994, The CCP4 Suite: Programs for Protein Crystallography. Acta Cryst D50: 760–763.
DeLano, W, 2002, The PyMOL User’s Manual, San Carlos, Ca, USA.
Fulop, V, Bocskei, Z and Polgar, L, 1998, Prolyl oligopeptidase: an unusual beta-propeller domain regulates proteolysis. Cell 94: 161–70.
Jones, TA, Zou, JY and Kjeldegaard, C, 1999, Improved Methods for binding protein models in electron density maps and the location of errors in these models. Acta Cryst. A47: 110–119.
Park, J, Ajami, K and Gorrell, MD (2005) Dipeptidyl peptidase 8 has post-proline dipeptidyl aminopeptidase, prolyl endopeptidase and acyl aminoacyl peptidase activities, In 2nd International Conference on Dipeptidyl Aminopeptidases.
Rasmussen, H, Branner, S, Wiberg, F and Wagtmann, N, 2002, Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog. Nat Struct Biol 10: 19–25.
Sali, A and Blundell, TL, 1993, Comparative protein modelling by satisfaction of spatial restraints. J M Biol 234: 779–815.
Thompson, JD, Gibson, TJ, Plewniak, F, Jeanmougin, F and G., HD, 1997, The ClustalX windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 24: 4876–4882.
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Pitman, M.R., Menz, R.I., Abbott, C.A. (2006). Prediction of Dipeptidyl Peptidase (DP) 8 Structure by Homology Modelling. In: Lendeckel, U., Reinhold, D., Bank, U. (eds) Dipeptidyl Aminopeptidases. Advances in Experimental Medicine and Biology, vol 575. Springer, Boston, MA . https://doi.org/10.1007/0-387-32824-6_4
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