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Mechanisms of Β- Lactamase Inhibition And MECHANISMS OF β- LACTAMASE INHIBITION AND HETEROTROPIC ALLOSTERIC REGULATION OF AN ENGINEERED β- LACTAMASE-MBP FUSION PROTEIN By WEI KE Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy. Dissertation Advisor: Dr. Focco ven den Akker Department of Biochemistry CASE WESTERN RESERVE UNIVERSITY May, 2011 CASE WESTERN RESERVE UNVERISTY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Wei Ke . candidate for the Ph.D degree*. (signed)Paul Carey . (chair of the committee) Focco van den Akker . Menachem Shoham . Robert A. Bonomo . Marion Skalweit . ___________________________________________ (date) 23 March, 2011 *We also certify that written approval has been obtained for any proprietary material contained therein. TABLE OF CONTENTS LIST OF TABLES ………………………………………………………………………8 LIST OF FIGURES ………………………………...…………………………………9 ACKNOWLEDGEMENTS ...………………………………………………………..13 LIST OF ABBREVIATIONS …………………...……………………………………15 ABSTRACT ……………………………….………………………………………...17 CHAPTER 1 Background and Significance …………………………………………....18 1.1 Antibiotic Resistance Crisis……………….…………………………….…...18 1.2 β-lactamases overview……………………………………………………….19 1.3 β-Lactam antibiotics and β-lactamase inhibitors ……………………………23 1.4 Structures of class A β –lactamases …………………………………………25 CHAPTER 2 Crystal Structures of SHV-1 β-Lactamase in Complex with Boronic Acid Transition State Inhibitors …………………………………………………...…….32 2.1 Introduction ………………………………………………………………….32 2.2 Materials and Methods ………………………………………………….…...34 2.2.1. Inhibitor synthesis and enzyme kinetics ……………….…………34 2.2.2. Enzyme purification ……………………………………...……….34 - 3 - 2.2.3. Crystallization and soaking.......................................................…...34 2.2.4. Data collection and structure determination ……………………...35 2.3 Results ……………………………………………………………………….36 2.3.1. Ceftazidime BATSI structure ………………………….…………38 2.3.2. Cefoperazone BATSI structure …………………………….…….39 2.3.3. Compound 1 and compound 2 structures …………………..…….40 2.4 Discussion ………………………………………………………….…..……41 Chapter 3 Crystal Structure of SHV-1 β-Lactamase in Complex with Penem and penam sulfone inhibitors that form cyclic inhibitory intermediates …………………….58 3.1 Introduction …………………………………………………………….……58 3.2 Materials and Methods ……………………………………………...……….60 3.2.1. Enzyme purification ………………………………………….…...60 3.2.2. Crystallization and soaking ......................................................…...60 3.2.3. Data collection and structure determination …………………...…60 3.3 Results and Discussion ……………………………………………..……….62 3.3.1. SHV-1: Penem 1 structure …………………………………..……62 3.3.2. SHV-1: SA1-204 structure ………………………………………..64 Chapter 4 Trans-Enamine Intermediate Formation as a β-Lactamase Inhibition Strategy Probed for Inhibitor-Resistant S130G SHV β-Lactamase...................................76 - 4 - 4.1 Introduction ..............................................................................................…...76 4.2 Materials and Methods ………………………………………………………78 4.2.1. Inhibitors..................................................................................…....78 4.2.2. Mutagenesis, purification and crystallization …………………….78 4.2.3. Soaking, data collection and structure determination …………….78 4.3 Results ......................................................................................................…...79 4.4 Discussion ……………………………………………………………..…….80 Chapter 5 Crystal Structure of KPC-2 β-Lactamase ………………………………..….88 5.1 Introduction …………………………………………………………….……88 5.2 Materials and Methods ………………………………………………………90 5.2.1. Enzyme expression and purification ……………………………...90 5.2.2. Crystallization ………….………………………………………....91 5.2.3. Data collection and structure determination …………………..….91 5.3 Results …………………………………………………………………….....93 5.4 Discussion ……………………………………………………………...……95 Chapter 6 Crystal Structure of KPC-2 β-Lactamase in Complex with 3-NPBA and PSR3-226 ………………………………………………………………...……….114 6.1 Introduction ………………………………………………………………...114 - 5 - 6.2 Materials and Methods ……………………………………………….…….115 6.2.1 Subcloning ………………………………………………….…....115 6.2.2 Expression and purification ……………………………………...116 6.2.3 Crystallization and soaking ………………………………………117 6.2.4 Data collection and structure determination ……………………..118 6.3 Results and Discussion……………………………………………………..118 6.3.1 KPC-2: 3-NPBA structure …………………………….…………118 6.3.2 KPC-2: PSR3-226 structure ……………………………….……..120 6.4 Conclusion..............................................................................................…...122 Chapter 7 Heterotropic Allosteric Regulation Mechanism of an Engineered β- Lactamase-MBP Fusion Protein………………………………………………………..131 7.1 Introduction ……………………………………………………..…………131 7.2 Materials and Methods …………………………………………………….133 7.2.1 Expression and purification ………………..…………………….133 7.2.2 Crystallization and soaking ……………………………….……...134 7.2.3 Data collection and structure determination ……………..………134 7.2.4 Molecular Dynamics Simulation ………………………….……..136 7.3 Results ………………………………………………………………….…..137 - 6 - 7.3.1 Overall structure ………………………………………………….137 7.3.2 Zinc binding ………………………………………………….…..139 7.3.3 MBP domain and TEM-1 domain ………………………….…….140 7.3.4 Mutagenesis………………………………………………….…...142 7.3.5 Molecular dynamics simulations of RG13……………………….143 7.4 Discussion…………………………………………………………….……144 7.4.1 Insights into maltose activation of RG13…………………..….145 7.4.2 General applicability of MBP as a sensory allosteric domain in fusion constructs……………………………………………………..149 7.4.3 Serendipitous zinc binding and regulation in RG13………..….151 Chapter 8 Summary and Future Directioins …………………………………………..174 8.1 Summary ………………………………………………………...…………174 8.2 Future directions …………………………………………………..……….180 Bibliography …………………………………………………………………………185 - 7 - LIST OF TABLES Table 2.1 Inhibition data for BATSI compounds…………………………………..56 Table 2.2 Data collection and refinement statistics…………………...……………57 Table 3.1 Data collection and refinement statistics………………………...………75 Table 4.1 Data collection and refinement statistics………………………….……..87 Table 5.1 Data collection and refinement statistics for KPC-2 structure………….111 Table 5.2 Active site distance changes of carbapenemases and non-carbapenemases.................................................................................................…...112 Table 5.3 Relative shifts in active site residues of carbapenemases compared to non-carbapenemases……………………………………………………………………113 Table 6.1 Inhibition and kinetics data………………..……………………………129 Table 6.2 Data collection and refinement statistics ……………………………....130 Table 7.1 Data collection and refinement statistics..........................................…...172 Table 7.2 Kinetics data from the literature……………………………..…………173 - 8 - LIST OF FIGURES Figure 1.1 Defense mechanisms of gram-negative bacteria against β-lactam antibiotics and β-lactamase inhibitors……………………………………...…..28 Figure 1.2 Typical structures in the β-lactam family are listed including the representative penicillin, cephalosporin, carbapenems and β-lactamase inhibitors ………………………………………………………………………….……..29 Figure 1.3 Crystal structure of SHV-1 β-lactamase (PDB ID: 1SHV)……… …..…30 Figure 2.1 Chemical structures of compounds and the synthesis scheme ...........…...49 Figure 2.2 Unbiased omit Fo-Fc maps……………………………………...……….50 Figure 2.3 Stereo view of interactions of the bound ligands within SHV-1 β-lactamase active site………………………………………………………………….. 51 Figure 2.4 Comparisons of β-lactamases and their bound BATSIs… …………...…53 Figure 3.1 Chemical structures and reaction schemes ……………………………...68 Figure 3.2 Electron density maps are depicted ……………………………………..70 Figure 3.3 Stereo view of interactions of the bound ligands within SHV-1 β-lactamase active site…………………………………………………………………...72 Figure 3.4 Structural superpositions ………………………...………………………73 Figure 4.1 Chemical structures of Clavulanic acid, tazobactam and SA2-13 and proposed reaction scheme of a generalized inhibitor with Class A β-lactamases based on previous work …………………………………………………………………….…..82 Figure 4.2 Electron density of the SA2-13 compound in the active site of S130G SHV-1 β-lactamase …………………………………………….………………………..83 - 9 - Figure 4.3 Stereo view of interactions of SA2-13 within S130G SHV β-lactamase active site……………………………………………………………………...…………84 Figure 4.4 All Cα superposition of SA2-13-S130G SHV with SA2-13-SHV-1……85 Figure 5.1 Schematic diagram of penicillin G, a carbapenem (imipenem), cephamycin (cefoxitin), a cephalosporin (cephalothin), and bicine………………..…..104 Figure 5.2 Electron density map………………………………..…………………..105 Figure 5.3 Structure of KPC-2 β-lactamase…………………………...………...…106 Figure 5.4 Stereo figure depicting the active site of KPC-2 with bicine and a superpositioned cephalosporin and schematic diagram of interactions of bicine in the active site of KPC-2………………………………………………………………….…107 Figure 5.5 Superposition of class A carbapenemases and the active sites of the carbapenemases and non-carbapenemase β-lactamases …………….…………………108 Figure 5.6 Active site adjustments of KPC-2 and their postulated role in accommodating cefoxitin……………………………………………………………….109 Figure 6.1 Chemical structures of the inhibitors and the proposed reaction scheme ……………………………………………………………………………..…. 123 Figure 6.2 Unbiased omit Fo-Fc maps contoured at 2.5σ are depicted ………………………………………………………….……………………..………. 124 Figure 6.3 Stereo view of interactions of the bound inhibitors within KPC-2 β- lactamase active site…………………………………………………………………….126 Figure
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