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Crystal Structure Analysis of a Snake Venom Metalloproteinase In Crystal structure analysis of a snake venom metalloproteinase in complex with an inhibitor as basis for considerations on the proteolytic activity and the hemorrhagic mode of action INAUGURALDISSERTATION zur Erlangung der Doktorwürde der Fakultät für Chemie, Pharmazie und Geowissenschaften Albert-Ludwigs Universität Freiburg im Breisgau vorgelegt von Torsten Jens Lingott aus Bayreuth Freiburg im Breisgau November 2010 Tag der Bekanntgabe des Prüfungsergebnisses: 16.12.2010 Dekan: Prof. Dr. H. Hillebrecht Referentin: Prof. Dr. I. Merfort Korreferent: Prof. Dr. J. M. Gutiérrez Drittprüfer: Prof. Dr. A. Bechthold Parts of this thesis have been or are prepared to be published in the following articles: Lingott, T., Schleberger, C., Gutiérrez, J. M., and Merfort, I. (2009). High-resolution crystal structure of the snake venom metalloproteinase BaP1 complexed with a peptidomimetic: insight into inhibitor binding. Biochemistry 48 , 6166-6174. Wallnoefer, H. G., Lingott, T., Gutiérrez, J. M., Merfort, I., and Liedl, K. R. (2010). Backbone flexibility controls the activity and specificity of a protein-protein interface: Specificity in snake venom metalloproteases. J Am Chem Soc 132 , 10330-10337. Lingott, T. and Merfort, I. (xxxx). The catalytic domain of snake venom metalloproteinases - Sequential and structural considerations. in preparation. Wallnoefer, H. G.*, Lingott, T.*, Escalante, T., Ferreira, R. N., Nagem, R. A. P., Gutiérrez, J. M., Merfort, I., and Liedl, K. R. (xxxx). The hemorrhagic activity of P-I snake venom metalloproteinases is controlled by loop dynamics. in preparation. * Equally contributed authors. Steinbrecher, T., Lingott, T., and Merfort, I. (xxxx). Free energy calculations on snake venom metalloproteinase BaP1. in preparation. Relevant coordinates and structure factors have been deposited in the RCSB Protein Data Bank under the following access codes: 2W12 High-resolution rystal structure of snake venom metalloproteinase BaP1 complexed with a peptidomimetic, 1.46 Å, pH 6.5 2W13 High-resolution rystal structure of snake venom metalloproteinase BaP1 complexed with a peptidomimetic, 1.14 Å, pH 4.6 2W14 High-resolution rystal structure of snake venom metalloproteinase BaP1 complexed with a peptidomimetic, 1.08 Å, pH 8.0 2W15 High-resolution rystal structure of snake venom metalloproteinase BaP1 complexed with a peptidomimetic, 1.05 Å, pH 7.5 Parts of this thesis have been presented at following conferences: Talk: Lingott, T., Wallnoefer, H. G., Liedl, K. R., Gutiérrez, J. M., and Merfort, I. (2010). In silico tool to predict hemorrhagic activity of snake venom metalloproteinases. 10 th Meeting of the Pan American Section of the International Society on Toxinology (IST) , San José, Costa Rica, April 18 th -20 th . Posters: Lingott, T., Gutiérrez, J. M., and Merfort, I. (2008). High-resolution crystal structure of the P-I snake venom metalloproteinase BaP1 in complex with a peptidomimetic: Insight into inhibitor binding. ChemBioNet - 5th Status Seminar Chemical Biology (DECHEMA e.V.) , Frankfurt, Germany, December 8 th -9th . Lingott, T., Gutiérrez, J. M., Wolber, G. and Merfort, I. (2009). High-resolution crystal structure of a SVMP*inhibitor complex as model for the design of metalloproteinase inhibitors. Drug Discovery and Delivery: Membrane Proteins and Natural Product Research , Freiburg, Germany, April 16 th -17 th . Lingott, T., Gutiérrez, J. M., Wolber, G. and Merfort, I. (2009). X-ray analysis of a snake venom metalloproteinase inhibitor complex as basis for drug design using pharmacophore-based virtual screening. Fakultätsfest der Fakultät für Chemie, Pharmazie und Geowissenschaften der Albert- Ludwigs-Universität , Freiburg, Germany, July 9th . Lingott, T., Gutiérrez, J. M., and Merfort, I. (2010). High-resolution crystal structure of the P-I SVMP BaP1 in complex with a peptidomimetic: Insight into inhibitor binding and importance of a flexible loop region correlated to hemorrhagic activity. 10 th Meeting of the Pan American Section of the International Society on Toxinology (IST) , San José, Costa Rica, April 18 th -20 th . Lingott, T., Wallnoefer, H. G., Liedl, K. R., Gutiérrez, J. M., and Merfort, I. (2010). Sequential and structural comparison of hemorrhagic and non-hemorrhagic P-I SVMPs and specific MD simulations lead to new insight into hemorrhagic activity. 10 th Meeting of the Pan American Section of the International Society on Toxinology (IST) , San José, Costa Rica, April 18 th -20 th . RESEARCH to see what everybody else has seen and to think what nobody else has thought Albert von Szent-Györgyi Nagyrápolt Table of contents 1 INTRODUCTION ........................................................................................................................1 1.1 Metalloendopeptidases.............................................................................................................1 1.1.1 Classification of zinc-dependent metalloendopeptidases.................................................2 1.1.2 The metzincin clan of metalloendopeptidases..................................................................3 1.1.3 Reaction mechanism of metzincins...................................................................................8 1.2 Metalloproteinases from snake venoms.................................................................................10 1.2.1 Classification and biosynthesis of snake venom metalloproteinases.............................11 1.2.2 Hemorrhagic activity of snake venom metalloproteinases.............................................16 1.3 Snake venom metalloproteinases as models for drug design.................................................17 1.4 In silico approaches in drug discovery...................................................................................18 1.4.1 Pharmacophore modeling and virtual screening...........................................................18 1.4.2 Protein-ligand docking...................................................................................................19 1.4.3 Molecular dynamics simulations....................................................................................19 1.4.4 Sequence alignments ......................................................................................................20 1.5 Aims of this work...................................................................................................................21 2 EXPERIMENTAL PROCEDURES.........................................................................................22 2.1 Materials ................................................................................................................................22 2.1.1 Appliances ......................................................................................................................22 2.1.2 Chemicals and kits .........................................................................................................23 2.1.3 Buffers and solutions......................................................................................................24 2.2 Protein purification ................................................................................................................26 2.2.1 Venom of Bothrops asper snakes ...................................................................................26 2.2.2 Ion exchange chromatography.......................................................................................26 2.2.3 Concentration of protein solutions.................................................................................27 2.2.4 Affinity chromatography ................................................................................................27 2.2.5 Gel permeation chromatography ...................................................................................28 2.3 Protein characterization .........................................................................................................29 2.3.1 Discontinuous sodium dodecylsulfate polyacrylamide gel electrophoresis...................29 2.3.2 Photometric determination of protein concentrations ...................................................29 2.3.3 Proteolytic activity of BaP1 and protease inhibition assay ...........................................30 2.4 Protein crystallization ............................................................................................................30 2.4.1 Crystal lattices and symmetry ........................................................................................30 2.4.2 Solvent content in protein crystals .................................................................................31 2.4.3 Protein crystallization....................................................................................................32 2.4.4 Crystal mounting............................................................................................................37 2.5 X-ray structure analysis .........................................................................................................38 2.5.1 Theory of X-ray diffraction ............................................................................................38 2.5.2 Reciprocal space and Ewald construction.....................................................................42 2.5.3 Temperature factors .......................................................................................................44 2.5.4 The Patterson function ...................................................................................................45
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