The discovery of the endogenous cannabinoid (CB) system, i.e. the CB receptors (the subtypes CB1 and CB2), endogenous ligands and enzymes for CB ligand metabolism, has triggered intensive pharmacological research into the CB receptors and the therapeutic potential of cannabinergic ligands. The CB2 receptor is known to be involved in the signal transduction cascades in the immune system, and has a great therapeutic potential for developing CB2 drugs without CB1-related psychotropic side effects for treatment of chronic neuro-pain, neuronal disorders, autoimmune diseases, and gliomas and other tumors of immune origin, thereby benefiting the millions of patients who suffer from the autoimmune/immune-related diseases for which we have no cure. Over the years, however, structural and functional studies of CB receptors have focused on predicting structures by computer modeling, identification of the specific sites for ligand binding and G-protein coupling whereas studies on experiment 3D CB structures are limited, in particular for the CB2 receptor. To understand the molecular mechanism behind these pharmacological and biochemical events, it is important to characterize the contacting points and binding domains and then elucidate the specific CB2/ligand recognition and CB2/G-protein coupling mechanisms at molecular structural level. In our published and pilot studies, we have successfully investigated the structural and conformational features of several CB2 protein functional domains;CB ligand structures and active pharmacophoric features;and agonist/antagonist recognition sites in the CB2 receptor. However, many questions still remain about CB2 receptor structure-function relationship as well as CB2 ligands and G-protein recognition mechanisms. The objective of this proposal is to identify/characterize the key residues/functional domains and elucidate their 3D structures of recognition pockets important to agonist and antagonist binding as well as G-protein coupling recognitions in the CB2 receptor by the combined biophysical and biochemical approaches. Our long term goal is to understand, in structural and functional terms, the molecular mechanisms of human CB2 activation and G-protein cell signaling process in order to facilitate the structure-based design for novel CB2 ligands. Having completed the """"""""proof-of-concept"""""""" research work, we propose the specific goals and in-depth research to three aims.
Aim 1 : Characterize the functional domains and key residues important to the CB2 ligand recognition and derive the structural determinants of the agonist/antagonist binding domains in the transmembrane and extra-cellular segments.
Aim 2 : Investigate and define the structural and functional features of the important CB2 intracellular segments and key residues involving G-protein coupling and intracellular cell signaling by the biophysical approaches developed and validated in Aim 1.
Aim 3 : Explore full-length CB2 receptor and confirm the key residues determined in Aims 1 and 2 and verify their importance to CB2 ligand recognition and G-protein coupling by functional binding assays and site-directed mutations of the native CB2 receptor. The elucidated CB2 agonist/antagonist recognition pockets and G-protein coupling domains will be further examined by our established computer modeling and receptor docking algorithms. Our proposed research and the outcomes will shed light onto a better understanding of CB2 structure/function and its mechanism of actions, and provide the structural bases for CB2-specific drug design in future. The techniques and methods developed from the proposed CB2 receptor research will also have a significant impact to other GPCRs.
This proposal is to identify and elucidate their 3D structures of recognition pockets important to agonist and antagonist binding as well as G-protein coupling recognitions in the cannabinoid CB2 receptor. The long-term benefits will allow us to better understand, in structural and functional terms, the molecular mechanisms of human CB2 activation and G-protein cell signaling process in order to facilitate structure-based design for novel CB2 chemical probes.
|Hu, Ziheng; Wang, Lirong; Ma, Shifan et al. (2018) Synergism of antihypertensives and cholinesterase inhibitors in Alzheimer's disease. Alzheimers Dement (N Y) 4:542-555|
|Bian, Yuemin; Feng, Zhiwei; Yang, Peng et al. (2017) Integrated In Silico Fragment-Based Drug Design: Case Study with Allosteric Modulators on Metabotropic Glutamate Receptor 5. AAPS J 19:1235-1248|
|Lee, Ji Young; Feng, Zhiwei; Xie, Xiang-Qun et al. (2017) Allosteric Modulation of Intact ?-Secretase Structural Dynamics. Biophys J 113:2634-2649|
|Chen, Si; Feng, Zhiwei; Wang, Yun et al. (2017) Discovery of Novel Ligands for TNF-? and TNF Receptor-1 through Structure-Based Virtual Screening and Biological Assay. J Chem Inf Model 57:1101-1111|
|Hu, Jianping; Hu, Ziheng; Zhang, Yan et al. (2016) Metal binding mediated conformational change of XPA protein:a potential cytotoxic mechanism of nickel in the nucleotide excision repair. J Mol Model 22:156|
|Feng, Zhiwei; Pearce, Larry V; Zhang, Yu et al. (2016) Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation. AAPS J 18:898-913|
|Hu, Jianping; Feng, Zhiwei; Ma, Shifan et al. (2016) Difference and Influence of Inactive and Active States of Cannabinoid Receptor Subtype CB2: From Conformation to Drug Discovery. J Chem Inf Model 56:1152-63|
|Zhang, Hai; Ma, Shifan; Feng, Zhiwei et al. (2016) Cardiovascular Disease Chemogenomics Knowledgebase-guided Target Identification and Drug Synergy Mechanism Study of an Herbal Formula. Sci Rep 6:33963|
|Teramachi, J; Silbermann, R; Yang, P et al. (2016) Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo. Leukemia 30:390-8|
|Feng, Rentian; Tong, Qin; Xie, Zhaojun et al. (2015) Targeting cannabinoid receptor-2 pathway by phenylacetylamide suppresses the proliferation of human myeloma cells through mitotic dysregulation and cytoskeleton disruption. Mol Carcinog 54:1796-806|
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