This International Collaboration in Chemistry (ICC) award in the Chemistry of Life Processes (CLP) program in the Division of Chemistry, supports collaborative work by Professors Brian Kobilka of Stanford University and Brian Shoichet of University of California, San Francisco in the United States, and Professor Takuya Kobayashi of Kyoto University in Japan, who is supported by the Japan Society for the Promotion of Science (JSPS). The goal of this proposal is to elucidate the chemical basis for the effect of allosteric ligands on muscarinic receptor structure and to develop new allosteric probes. Muscarinic receptors are members of the family of G protein coupled receptors (GPCRs). GPCRs are nature's most versatile chemical sensors. There are over 800 GPCRs in the human genome and they respond to a broad spectrum of chemical entities. Among the large family of GPCRs, the muscarinic receptors stand out for their ability to detect and respond to two distinct chemical entities that interact with two different binding sites: the orthosteric and allosteric binding pockets. The orthosteric binding pocket is the binding site for the neurotransmitter acetylcholine. The amino acids that form the orthosteric binding site are highly conserved among all five muscarinic receptor subtypes. As such, developing subtype selective chemical probes that regulate muscarinic receptor function has not been successful. There is a higher degree of chemical diversity outside of the orthosteric site including potential allosteric binding sites. Thus, allosteric ligands have the potential for highly subtype-selective chemical interactions with receptors. However, much less is known about the structural basis of allosteric ligand binding or how chemical interactions between amino acids that form this allosteric site and allosteric ligands lead to changes in receptor function.
The collaborative US-Japanese team will use the M2 muscarinic receptor as a model system for the proposed project, the methods developed during this collaboration will be generally applicable to other GPCRs, and allosteric tools developed during this project may ultimately be developed into more effective therapeutics. The proposed research will take advantage of complementary expertise in the three collaborating labs using pharmacological, biophysical and computational approaches to develop new highly selective chemical tools that can be used to modulate the activity of muscarinic receptors. Postdoctoral fellows from the three collaborating institutions will gain experience in all aspects of the proposed research.
