Editorial pubs.acs.org/CR
Introduction: G-Protein Coupled Receptors osome”8a ligand, receptor, and accessory signaling protein in a biological membranemust be addressed by interrogating a structure using computational or biophysical approaches. And one of the dominant issues a decade ago, namely the role of receptor oligomerization in function, also remains an open issue for many receptor types.
M
ore than 15 years have passed since the publication of the first crystal structure of a G-protein coupled receptor (GPCR),1 and nearly a decade ago the first structures of an expressed recombinant GPCR were reported.2,3 Now approximately 40 unique GPCR high-resolution crystal structures are available in complex with a variety of ligands, some with stabilizing nanobodies, and others in complex with accessory signaling proteins.4,5 Given the success of technology applications that facilitate studies of membrane proteins, such as lipidic cubic phase enabled crystallization6 and screening methods, thermal stabilization through mutagenesis, and more recently serial femtosecond crystallography,7 it is conceivable that structures will become available, in one form or another, for each one of the 826 (or so) human GPCRsall potential targets for therapeutic drugs. So in many ways, we are now at the dawn of the “post structural biology” era for GPCR research. New GPCR structures will continue to come, but now the real question is how do we use the structures to understand how GPRCs really work? For example, structures themselves in isolation do not necessarily provide insights about modulation of receptor signaling by allosteric modulatorssmall molecules, lipids, and ions that bind at a site distant from the orthosteric binding pocket of the endogenous agonist. Allosteric modulation of GPCRs is a now well-established concept in pharmacology that provides new opportunities for drug discovery, but at the same time has created challenges in terms of adapting earlier formalisms to new understanding of the structural and theoretical aspects of allosteric modulation. In many cases, allosteric ligands, either “positive” or “negative”, overlap with the binding site of orthosteric ligands. However, many allosteric GPCR ligands have also been identified that appear to bind at sites with no topological overlap with primary orthosteric sites. Of course, the effects of lipids, cholesterol, and cations (including sodium) can affect the ligand-induced signaling activity of GPCRs (some more than others), and notably, the binding of cytoplasmic signal transducers, like G proteins, also affects the apparent binding affinities of agonist ligands. In fact, given that a GDP-bound G protein generally can form a ternary complex with its cognate GPCR and cause the receptor to bind agonist in its “high-affinity” state, it might not be shocking that a small molecule might do something similar. However, the structural basis of allosteric modulation of GPCRs will continue to be a major topic of study in the future. In addition, structures alone do not directly address the very interesting issue of signaling bias. Why do some agonist ligands activate preferentially, for example, heterotrimeric G protein pathways while others activate β-arrestin signaling? A related issue is that despite the existence of structures from GPCRs that signal dominantly through a particular class of G proteins, for example Gs or Gi/o, it remains challenging in the absence of direct cell based assay data to determine, based on primary structures or even crystal structures, which G protein subtype will couple to a particular receptor. Finally, the issue of receptor dynamics within the functional unit known as the “signal© 2017 American Chemical Society
TOPICS REVIEWED The key topics introduced above are all dealt with in detail in the excellent collection of articles in this thematic issue. Two broad themes related to the molecular pharmacology of GPCRs are emphasized and interleafed throughout the issue. First, functional aspects of GPCRs based on chemical principles, including concepts of allosterism, biased signaling, and receptor theory, are covered. Second, structure-based studies, including structural biology, structure-based drug discovery, and structure-based dynamics, are covered. A major focus of the articles in the issue involves new chemical approaches and methodologies. Terry Kenakin covers theoretical aspects of the complex pharmacology of GPCR−ligand complexes and provides useful approaches about how mathematical models can be used to describe complex drug−receptor interactions. Then Ali Jazayeri, Stephen Andrews, and Fiona Marshall provide an excellent review of how GPCR structures enable drug discovery. They use the adenosine A2A receptor as a kind of molecular case report and highlight key developments in the field. Adriaan Ijzerman and colleagues Dong Guo and Laura Heitman provide a comprehensive discussion of how cell-based and in vitro assays can be used to determine kinetic and structure−activity relationships in adenosine receptors. Graeme Milligan, Brian Hudson and colleagues Bharat Shimpukade and Trond Ulven tackle one of the most difficult and complicated families of GPCRsthe “free” fatty acid receptors (FAARs) that are activated by nonesterified fatty acids. Many FAARs have recently been “deorphanized” and are the subject of intense drug discovery efforts. Family B GPCRs, which respond to paracrine or endocrine peptide hormones, are covered, with a focus on allosterism and biased agonism in a comprehensive article by Denise Wootten, Laurence Miller, and Patrick Sexton along with Cassandra Koole and Arthur Christopoulos. The final three articles in the issue deal more with general computational and chemical biological methods. Ron Dror, along with Naomi Latorraca and A. J. Venkatakrishnan, summarize and contextualize the major contributions that computational approaches have contributed to understanding GPCR dynamics. They focus primarily on high-performance computing that can provide all-atom views of receptor and ligand dynamics over relatively long time scales (up to milliseconds in some remarkable cases). Xavier Periole then describes the development of a complementary method and Special Issue: G-Protein Coupled Receptors Published: January 11, 2017 1
DOI: 10.1021/acs.chemrev.6b00686 Chem. Rev. 2017, 117, 1−3
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Editorial
AUTHOR INFORMATION
shows how coarse grain molecular dynamics simulations can be used to study very large systems of receptors, even in complex with accessory proteins, in model membrane bilayers. Finally, Thomas Huber along with He Tian and Alexandre Fürstenberg provide a comprehensive update and review about how experimental chemical biology tools under development can be applied to single-molecule imaging methods to study GPCRs. The unique and novel approaches that they report, including effective bioorthogonal labeling strategies, will have a significant impact on future studies of GPCR pharmacology because single molecule approaches are often needed to elucidate kinetic properties of receptor−ligand interactions that might underlie ligand signaling bias.
Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS. Biography
DEFINITIONS At the beginning of this project, we had a lively discussion about the title of the subject of this issue of Chemical Reviews. Some authors pointed out that the term GPCR, after nearly 30 years of continuous use, might be getting a bit stale, especially since it is clear that GPCRs signal, not only through heterotrimeric G proteins, but also through multiple other cellular signaling pathways. Perhaps the term seven-transmembrane (7-TM) helical receptor would be more timely and appropriate. However, 7-TM helical receptors can also refer broadly to entirely different types of membrane proteins, including channelrhodopsins, sensory rhodopsins, and lightdriven ion pumps, such as halorhodopsins and bacteriorhodopsins, which are not, in fact, GPCRs. These proteins are not found in humans but have been the subject of intense study because of their exceedingly interesting biology and biophysics, and also more recently because of their potential applications to the burgeoning field of optogenetics. Optogenetics, beyond its role as a method in basic neuroscience research, is also now being used as a drug discovery tool.9 In addition, the 7-TM receptor category would also encompass the human adiponectin receptor family,10 and also the enormous family of insect odorant receptors,11 among other receptor families. Interestingly, both the adiponectic receptors and the insect odorant receptors are “inverted” in the membrane compared with the topology of GPCRs. Unlike GPCRs, they have the aminoterminal tail on the outside of the cell, and the carboxy-terminal tail on the inside. Given their inverted membrane topology, these 7-TM receptors do not couple to G proteins, but their precise signaling mechanism remains to be determined.
Thomas P. Sakmar is a physician−scientist and the Richard M. & Isabel P. Furlaud Professor and Head of the Laboratory of Chemical Biology & Signal Transduction at The Rockefeller University in New York. He is also a Guest Professor at the Karolinska Institutet in Stockholm and recently held the Marie Krogh Visiting Professorship at University of Copenhagen. Dr. Sakmar’s multidisciplinary research program is focused on understanding how cells communicate with each other and how organisms sense their environment. The common theme in all of these processes is called “signal transduction”, and the CPCRs on the cell surface that mediate signaling are important targets of therapeutic drugs. Dr. Sakmar received his A.B. degree in chemistry from the University of Chicago and his M.D. degree from the University of Chicago Pritzker School of Medicine. While attending a N.A.T.O. Advanced Studies Institute course on membrane biophysics in France in 1979, Dr. Sakmar was inspired by Martin Rodbell, who had just coined the term “signal transduction” and went on to win a Nobel Prize in 1984. Dr. Sakmar completed a residency in internal medicine at the Massachusetts General Hospital, Boston, and conducted postdoctoral research in the laboratory of Nobel Prize winner H. Gobind Khorana in the Department of Chemistry at the Massachusetts Institute of Technology. During his research training at MIT, Dr. Sakmar was among the first scientists to employ techniques of molecular biology, such as site-directed mutagenesis and heterologous expression, to study GPCRs. Dr. Sakmar was recruited by David Baltimore to join Rockefeller University in 1990. He was promoted to Professor with tenure in 1998 and received the Furlaud endowed chair in 2002. Dr. Sakmar has been an Investigator of the Howard Hughes Medical Institute in their Neuroscience Program and a Senior Scholar of the Ellison Medical Foundation. He is also a Senior Physician in The Rockefeller University Hospital, a major NIH-funded Clinical and Translational Research Center, and served as Associate Dean in charge of the M.D.−Ph.D. Program. Dr. Sakmar was Acting President of Rockefeller University for 19 months in 2002−2003. While Acting President, he recruited several exceptional faculty members, including C. David Allis, Tom Tuschl, and Cori Bargmann, wrapped up a successful fund raising campaign, and founded a privately funded human embryonic stem cell initiative. He has served on numerous academic, institutional, and governmental committees and panels and has consulted widely for the biotechnology and pharmaceutical industry, including serving on the scientific advisory boards of Leukosite, Inc., Natural Pharmaceuticals, Inc., Resolvyx, Inc., and Anchor Therapeutics, Inc. He is currently on the Board of the Helen
CONCLUDING REMARKS It is never possible to cover a field as broad as GPCR pharmacology in a single volume, nor is it possible to be scrupulously up to date in a comprehensive review journal. However, the unique format of Chemical Reviews, along with an unusually punctual group of contributing authors, has allowed us to provide a timely snapshot of the current state of GPCR pharmacology with a focus on chemistry in this early poststructural era. Research “targeting” GPCRs (as the cover art indicates) has been an important area of biology and chemistry in both academic and industrial settings for decades, and as demonstrated in this issue of Chemical Reviews, it will remain an exciting and productive field of multidisciplinary chemistry research for years to come. Thomas P. Sakmar The Rockefeller University 2
DOI: 10.1021/acs.chemrev.6b00686 Chem. Rev. 2017, 117, 1−3
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M.; Yamauchi, T.; Kadowaki, T.; Yokoyama, S. Crystal structures of the human adiponectin receptors. Nature 2015, 520, 312−316. (11) Hopf, T. A.; Morinaga, S.; Ihara, S.; Touhara, K.; Marks, D. S.; Benton, R. Amino acid coevolution reveals three-dimensional structure and functional domains of insect odorant receptors. Nat. Commun. 2015, 6, 6077−6083.
Hay Whitney Foundation and was a Director of The Medical Letter, a nonprofit drug evaluation newsletter with nearly 300,000 physician subscribers. Dr. Sakmar lives in New York City and Stockholm with his wife Karina Åberg, twin daughters (age 13), and son (age 12).
ACKNOWLEDGMENTS I want to express my thanks and gratitude to Prof. Ruma Banerjee, University of Michigan, who serves as Associate Editor of Chemical Reviews and who helped me to formulate this thematic issue. Lou Larsen handled much of the editor burden with aplomb and good humorextremely welcome traits when dealing with a large group of very busy scientists and his help is very much appreciated. Of course, I thank all of the authors, many of whom I have known for many years, and some I have just recently met, for contributing outstanding, creative, and scholarly articles. Special thanks and acknowledgment also goes to Karina Åberg, an artist and designer, who prepared the cover art. It has been a pleasure for me to work on this project with such a remarkable team of editors and authors. REFERENCES (1) Palczewski, K.; Kumasaka, T.; Hori, T.; Behnke, C. A.; Motoshima, H.; Fox, B. A.; Le Trong, I.; Teller, D. C.; Okada, T.; Stenkamp, R. E.; Yamamoto, M.; Miyano, M. Crystal Structure of rhodopsin: a G protein-coupled receptor. Science 2000, 289, 739−745. (2) Rasmussen, S. G.; Choi, H. J.; Rosenbaum, D. M.; Kobilka, T. S.; Thian, F. S.; Edwards, P. C.; Burghammer, M.; Ratnala, V. R.; Sanishvili, R.; Fischetti, R. F.; Schertler, G. F.; Weis, W. I.; Kobilka, B. K. Crystal structure of the human β2 adrenergic G-protein-coupled receptor. Nature 2007, 450, 383−387. (3) Cherezov, V.; Rosenbaum, D. M.; Hanson, M. A.; Kobilka, B. K.; Stevens, R. C. High resolution crystal structure of an engineered Human β2-adrenergic G protein-coupled receptor. Science 2007, 318, 1258−1265. (4) Rasmussen, S. G.; DeVree, B. T.; Zou, Y.; Kruse, A. C.; Chung, K. Y.; Kobilka, T. S.; Thian, F. S.; Chae, P. S.; Pardon, E.; Calinski, D.; Mathiesen, J. M.; Shah, S. T.; Lyons, J. A.; Caffrey, M.; Gellman, S. H.; Steyaert, J.; Skiniotis, G.; Weis, W. I.; Sunahara, R. K.; Kobilka, B. K. Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 2011, 477, 549−555. (5) Shukla, A. K.; Manglik, A.; Kruse, A. C.; Xiao, K.; Reis, R. I.; Tseng, W. C.; Staus, D. P.; Hilger, D.; Uysal, S.; Huang, L. Y.; Paduch, M.; Tripathi-Shukla, O.; Koide, A.; Koide, S.; Weis, W. I.; Kossiasoff, A. A.; Kobilka, B. K.; Lefkowitz, R. J. Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature 2013, 497, 137−141. (6) Caffrey, M.; Cherezov, V. Crystallizing membrane proteins using lipidic mesophases. Nat. Protoc. 2009, 4, 706−731. (7) Liu, W.; Wacker, D.; Gati, C.; Han, G. W.; James, D.; Wang, D.; Nelson, G.; Weierstall, U.; Katritch, V.; Barty, A.; Zatsepin, N. A.; Li, D.; Messerschmidt, M.; Boutet, S.; Williams, G. J.; Koglin, J. E.; Seibert, M. M.; Wang, C.; Shah, S. T.; Basu, S.; Fromme, T.; Kuptiz, C.; Rendek, K. N.; Grotjohann, I.; Fromme, P.; Kirian, R. A.; Beyerlein, K. R.; White, T. A.; Chapman, H. H.; Caffrey, M.; Spence, J. C.; Stevens, R. C.; Cherezov, V. Serial femtosecond crystallography of G protein-coupled receptors. Science 2013, 342, 1521−1524. (8) Huber, T.; Sakmar, T. P. Chemical biology methods for investigating G protein-coupled receptor signaling. Chem. Biol. 2014, 21, 1224−1237. (9) Song, C.; Knöpfel, T. Optogenetics enlightens neuroscience drug discovery. Nat. Rev. Drug Discovery 2016, 15, 97−109. (10) Tanabe, H.; Fujii, Y.; Okada-Iwabu, M.; Iwabu, M.; Nakamura, Y.; Hosaka, T.; Motoyama, K.; Ikeda, M.; Wakiyama, M.; Terada, T.; Ohsawa, N.; Hato, M.; Ogasawara, S.; Hino, T.; Murata, T.; Iwata, S.; Hirata, K.; Kawano, Y.; Yamamoto, M.; Kimura-Someya, T.; Shirouzu, 3
DOI: 10.1021/acs.chemrev.6b00686 Chem. Rev. 2017, 117, 1−3
