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Structural Studies of the Interaction Between Mglu5 And STRUCTURAL STUDIES OF THE INTERACTION BETWEEN MGLU5 AND ALLOSTERIC MODULATORS By Elizabeth Dong Nguyen Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Chemical and Physical Biology August, 2013 Nashville, Tennessee Approved: Professor Walter J. Chazin Professor P. Jeffrey Conn Professor Terry P. Lybrand Professor David L. Tabb Copyright © 2013 by Elizabeth Dong Nguyen All Rights Reserved ACKNOWLEDGEMENTS The work presented here was made possible by Public Health Service award T32 GM07347 from the National Institute of General Medical Studies for the Vanderbilt Medical-Scientist Training Program (MSTP), the Paul Calabresi Medical Student Research Fellowship from the Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation and a Deutscher Akademischer Austausch Dienst (DAAD) research grant from the German Academic Exchange Service. Computational resources were provided by the Advanced Computing Center for Research and Education and the Center for Structural Biology at Vanderbilt University. I would like to thank my advisor, Dr. Jens Meiler, who fostered in me the desire to pursue research as a summer undergraduate student and continued to support, guide and mentor me through my graduate studies. His excitement for science is infectious and has inspired my own ambitions to spread the passion of science to others. I would like to thank other faculty members who aided in my scientific growth while at Vanderbilt University, particularly my committee members: Dr. Walter Chazin, Dr. Jeff Conn, Dr. Terry Lybrand and Dr. David Tabb. They have continually provided guidance and encouragement for my research progress and career development. The Vanderbilt MSTP program has been a steady and consistent source of support and the strongest advocates for my success. I’m thankful to Dr. Terry Dermody for initially recruiting me into the program and for continual inspiration, as well as Dr. Michelle Grundy, Dr. Jim Bills, Dr. Larry Swift and Melissa Krasnove for their continual support. Thanks also to my MSTP mentor Dr. Dan Roden, who supported me from the day I interviewed at Vanderbilt. The Vanderbilt Chemical and Physical Biology program has been instrumental iii to my success in graduate school and I’d like to thank the following members for their help: Dr. Hassane Mchaourab, Dr. Al Beth, Dr. Bruce Damon and Lindsay Meyers. I want to say a special thank you to Dr. Karen Gregory from the Conn lab for her mentorship. She taught me everything I know about the wet lab and was instrumental in helping me put together my thesis work. I am ever grateful for her guidance and all I learned from her about being a great scientist. I’d also like to thank Sabuj, Roy, Jarrod and Jonathan from the Center of Structural Biology for their computational expertise. Current and former members of the Meiler lab have been invaluable as friends and colleagues, both in the lab and outside of it. Dr. Julia Leman has been a wonderful friend and her encouragement has shaped my growth as a scientist and a person. My thanks also go out Stephanie DeLuca and Dr. Nathan Alexander of Room 5154G for support on a daily basis. For everyone else in the lab who patiently answered my questions and with whom I’ve been to the mountains and beach together and back, I’m thankful as well. I am certain I have the best MSTP class, whom I consider my family here in Nashville, particularly Frances, Eric, Tanner, John, Brian, & Caroline. Additionally, my friends from around the world have been there for me in the best and worst of times and for their support and prayers I am eternally grateful: Linda, Lisa, Elaine, Suzanne, Mari, Lauren, Anna, Veronica, Thuy, Meryl and many more. I have been blessed with the most wonderful family. My husband, Kevin Nguyen, has been by my side as a source of love and support from the moment I embarked on this journey. I couldn’t have done any of this without him. My dad (Hoa), mom (Lori), sister (Emily) and brother (Jon) have always been an inspiration to me and my strongest supporters. I strive to be more like them each day. Above all, I am thankful to my God for filling me with strength, love, hope and purpose (Jeremiah 29.11). iv TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ................................................................................................ iii LIST OF TABLES ............................................................................................................. ix LIST OF FIGURES ........................................................................................................... xi SUMMARY ..................................................................................................................... xvi Chapter I. INTRODUCTION ................................................................................................... 1 G protein-coupled receptors as therapeutic targets ................................... 1 Targeting the metabotropic glutamate receptor subtype 5 for cognitive function disorders ...................................................................................... 3 Detecting the binding site for allosteric modulators ................................... 8 Structural analysis of G protein-coupled receptors .................................. 12 Current computational methods for G protein-coupled receptor structure prediction ................................................................................................. 15 Computational methods for small-molecule docking ............................... 18 Predicting interactions between G protein-coupled receptors and small molecules by combining experimental data with computational predictions ................................................................................................................. 19 II. SMALL-MOLECULE LIGAND DOCKING INTO COMPARATIVE MODELS WITH ROSETTA ........................................................................................................... 23 Summary ................................................................................................. 23 Introduction .............................................................................................. 24 Experimental design ................................................................................ 32 Anticipated results ................................................................................... 46 Author Contributions ................................................................................ 52 Acknowledgements.................................................................................. 53 III. ASSESSMENT AND CHALLENGES OF LIGAND DOCKING INTO COMPARATIVE MODELS OF G PROTEIN-COUPLED RECEPTORS ............. 54 v Summary ................................................................................................. 54 Introduction .............................................................................................. 55 Methods ................................................................................................... 57 Results and Discussion ........................................................................... 66 Concluding Remarks ............................................................................... 94 Acknowledgments.................................................................................... 98 IV. PROBING THE METABOTROPIC GLUTAMATE RECEPTOR 5 (MGLU5) POSITIVE ALLOSTERIC MODULATOR (PAM) BINDING POCKET: DISCOVERY OF POINT MUTATIONS THAT ENGENDER A “MOLECULAR SWITCH” IN PAM PHARMACOLOGY ................................................................ 99 Summary ................................................................................................. 99 Introduction ............................................................................................ 100 Materials ................................................................................................ 102 Results ................................................................................................... 108 Discussion ............................................................................................. 133 V. INVESTIGATING THE BINDING MODES OF METABOTROPIC GLUTAMATE RECEPTOR 5 (MGLU5) ALLOSTERIC MODULATORS FROM DIVERSE SCAFFOLDS ..................................................................................................... 139 Summary ............................................................................................... 139 Introduction ............................................................................................ 140 Materials and Methods .......................................................................... 144 Results and Discussion ......................................................................... 151 Conclusions ........................................................................................... 160 VI. CHARACTERIZING THE ROLE OF CYSTEINE RESIDUES ON METABOTROPIC GLUTAMATE RECEPTOR 5 (MGLU5) FUNCTION ........... 164 Summary ............................................................................................... 164 Introduction ............................................................................................ 165 Materials and Methods .......................................................................... 168 Results ..................................................................................................
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