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Gpcr Structure

X Edward Zhou, Karsten Melcher, H Eric Xu
G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors that mediate numerous cell signaling pathways, and are targets of more than one-third of clinical drugs. Thanks to the advancement of novel structural biology technologies, high-resolution structures of GPCRs in complex with their signaling transducers, including G-protein and arrestin, have been determined. These 3D complex structures have significantly improved our understanding of the molecular mechanism of GPCR signaling and provided a structural basis for signaling-biased drug discovery targeting GPCRs...
October 12, 2018: Protein Science: a Publication of the Protein Society
H C Stephen Chan, Jingjing Wang, Krzysztof Palczewski, Slawomir Filipek, Horst Vogel, Zhi-Jie Liu, Shuguang Yuan
Identifying a target ligand binding site is an important step for structure-based rational drug design as shown here for G protein-coupled receptors (GPCRs), which are among the most popular drug targets. We applied long-time scale molecular dynamics simulations, coupled with mutagenesis studies, to two prototypical GPCRs, the M3 and M4 muscarinic acetylcholine receptors. Our results indicate that unlike synthetic antagonists, which bind to the classic orthosteric site, the endogenous agonist acetylcholine is able to diffuse into a much deeper binding pocket...
August 21, 2018: Chemical Science
Xianjun Zhang, Shaowei Dong, Fei Xu
Class Frizzled G protein-coupled receptors (GPCRs), which includes the Smoothened receptor (SMO) and 10 Frizzled receptors (FZDs), are responsible for mediating fundamental signaling in embryonic development and tissue homeostasis. Dysregulation of these receptors can lead to cancer. Structural understanding of these molecules has provided insight to their function and signaling, and guided drug discovery. To date, the structures of the multi- and individual domains of SMO, 14 FZD extracellular domains, and the transmembrane domain (TMD) of FZD4, have been reported...
October 8, 2018: Trends in Biochemical Sciences
Krishna A Gajjar, Anuradha K Gajjar
Pharmacophore mapping and molecular docking can be synergistically integrated to improve the drug design and discovery process. A rational strategy, combiphore approach, derived from the combined study of Structure and Ligand based pharmacophore has been described to identify novel GPR40 modulators. DISCOtech module from Discovery studio was used for the generation of the Structure and Ligand based pharmacophore models which gave hydrophobic aromatic, ring aromatic and negative ionizable as essential pharmacophoric features...
October 8, 2018: Current Drug Discovery Technologies
Douglas D Lopes, Jamille H Cuvero, Mariana M L Ferreira, Rogério L Silva, Sinval E G Souza, Luciana Malavolta, Shirley Schreier, Clovis R Nakaie
We compared the synthesis and structural/conformational details of the (66-97) segments of the second transmembrane helix of AT1, MAS and B2, all of which belong to the class of G-protein-coupled receptors (GPCR). Step-by-step monitoring of the coupling reactions during the growth of these transmembrane peptides revealed that the increase in the level of difficulty started at the 6-10 regions of the sequence. Possibly due to their long and hydrophobic sequences, the final estimated synthesis yields decreased progressively by up to 20-25%...
October 8, 2018: Amino Acids
Xianqiang Sun, Sukrit Singh, Kendall Blumer, Gregory R Bowman
Activation of heterotrimeric G proteins is a key step in many signaling cascades. However, a complete mechanism for this process, which requires allosteric communication between binding sites that are ~30 Å apart, remains elusive. We construct an atomically-detailed model of G protein activation by combining three powerful computational methods: metadynamics, Markov state models (MSMs), and CARDS analysis of correlated motions. We uncover a mechanism that is consistent with a wide variety of structural and biochemical data...
October 5, 2018: ELife
Fariba M Assadi-Porter, James Radek, Hongyu Rao, Marco Tonelli
Taste signaling is a complex process that is linked to obesity and its associated metabolic syndromes. The sweet taste is mediated through a heterodimeric G protein coupled receptor (GPCR) in a species-specific manner and at multi-tissue specific levels. The sweet receptor recognizes a large number of ligands with structural and functional diversities to modulate different amplitudes of downstream signaling pathway(s). The human sweet-taste receptor has been extremely difficult to study by biophysical methods due to the difficulty in producing large homogeneous quantities of the taste-receptor protein and the lack of reliable in vitro assays to precisely measure productive ligand binding modes that lead to activation of the receptor protein...
October 3, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Arfaxad Reyes-Alcaraz, Yoo-Na Lee, Seongsik Yun, Jong-Ik Hwang, Jae Young Seong
Discovery of biased ligands and receptor mutants allows characterization of G-protein- and β-arrestin-mediated signaling mechanisms of G-protein-coupled receptors (GPCRs). However, the structural mechanisms underlying biased agonism remain unclear for many GPCRs. We show that while Galanin induces the activation of the galanin receptor 2 (Galr2) that leads to a robust stimulation toward Gαq-protein and β-arrestin1/2, an alternative ligand Spexin and its analog have biased agonism toward G-protein signaling relative to Galanin...
2018: Communications biology
Louis-Philippe Picard, Anne Marie Schönegge, Martin J Lohse, Michel Bouvier
G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate a variety of cellular response which make them a target of choice for drug development in many indications. It is now well established that GPCRs can adopt several distinct conformations that can be differentially stabilized by various ligands resulting in different biological outcomes, a concept known as functional selectivity. However, due to the highly hydrophobic nature of GPCRs, tools to monitor these conformational ensembles are limited and addressing their conformation dynamics remains a challenge with current structural biology approaches...
2018: Communications biology
Mahmoud A A Ibrahim, Alaa M A Hassan
Leukotriene B4 (LTB4) exerts its biological effects through stimulation of specific G protein-coupled receptors (GPCRs)-namely BLT1 and BLT2. Due to the absence of human BLT1 and BLT2 crystal structures, the current study was set to predict the 3D structures of these two receptors for structure-based anti-inflammatory drug discovery. Homology modeling of the BLT1 receptor was first constructed, based on various X-ray and NMR GPCR templates, followed by molecular dynamics (MD) refinement. Using a single-template approach, nine well-established alignment methods and ten secondary structure prediction methods during the backbone generation were implemented and assessed...
September 28, 2018: Protein Journal
Haiyi Chen, Weitao Fu, Zhe Wang, Xuwen Wang, Tailong Lei, Feng Zhu, Dan Li, Shan Chang, Lei Xu, Tingjun Hou
The number of solved G protein-coupled receptor (GPCR) crystal structures has expanded rapidly, but most GPCR structures remain unsolved. Therefore, computational techniques, such as homology modeling, have been widely used to produce the theoretical structures of various GPCRs for structure-based drug design (SBDD). Due to the low sequence similarity shared by the transmembrane domains of GPCRs, accurate prediction of GPCR structures by homology modeling is quite challenging. In this study, angiotensin II type I receptor (AT1R) was taken as a typical case to assess the reliability of class A GPCRs homology models for SBDD...
September 28, 2018: ACS Chemical Neuroscience
Raphael Alhadeff, Igor Vorobyov, Han Wool Yoon, Arieh Warshel
G-protein-coupled receptors (GPCRs) are a large group of membrane-bound receptor proteins that are involved in a plethora of diverse processes (e.g., vision, hormone response). In mammals, and particularly in humans, GPCRs are involved in many signal transduction pathways and, as such, are heavily studied for their immense pharmaceutical potential. Indeed, a large fraction of drugs target various GPCRs, and drug-development is often aimed at GPCRs. Therefore, understanding the activation of GPCRs is a challenge of major importance both from fundamental and practical considerations...
September 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
Robert Adamu Shey, Stephen Mbigha Ghogomu, Ferdinand Ngale Njume, Lea Olive Tchouate Gainkam, Philippe Poelvoorde, Leon Mutesa, Annie Robert, Perrine Humblet, Jean-Pierre Munyampundu, Joseph Kamgno, Christophe Lelubre, Luc Vanhamme, Jacob Souopgui
Onchocerciasis is a severely debilitating yet neglected tropical disease (NTD) that creates social stigma, generates and perpetuates poverty, and leads ultimately in some cases to irreversible unilateral or bilateral blindness if untreated. Consequently, the disease is a major impediment to socioeconomic development. Many control programs have been launched for the disease with moderate successes achieved. This mitigated hit is partially due to the lingering need for reliable, non-invasive and easily applicable tools for mapping endemic regions and post-elimination surveillance...
2018: PloS One
Ching-Ju Tsai, Filip Pamula, Rony Nehmé, Jonas Mühle, Tobias Weinert, Tilman Flock, Przemyslaw Nogly, Patricia C Edwards, Byron Carpenter, Thomas Gruhl, Pikyee Ma, Xavier Deupi, Jörg Standfuss, Christopher G Tate, Gebhard F X Schertler
Selective coupling of G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) to specific Gα-protein subtypes is critical to transform extracellular signals, carried by natural ligands and clinical drugs, into cellular responses. At the center of this transduction event lies the formation of a signaling complex between the receptor and G protein. We report the crystal structure of light-sensitive GPCR rhodopsin bound to an engineered mini-Go protein. The conformation of the receptor is identical to all previous structures of active rhodopsin, including the complex with arrestin...
September 2018: Science Advances
Bice Chini
Neuropeptide signalling is primarily based on activation of G protein-coupled receptors (GPCRs), the largest family of membrane receptors. GPCRs are involved in multiple physiological processes and are important drug targets for many human diseases. In this at a glance review, we focus on the recent advances in GPCR signalling related to the different structural and functional features of complexes involved in G protein- and arrestin-mediated signalling, receptor dimerization and oligomerization, modulation and transactivation of other signalling proteins and receptor compartimentalization...
September 22, 2018: Cell and Tissue Research
P Thangarasu, S Thamarai Selvi, A Manikandan
In the present study, novel 2-cyclopropyl-3-ethynyl-4-(4-fluorophenyl) quinolines (4a-l) were recognized and evaluated as G-Protein Coupled Receptor (GPCR) ligands through molecular evaluations. Thrombin mediates adhesion of mast cell, a type of cell abundantly found in connective tissue and releasing histamine and other substances during inflammatory and allergic reactions, through phosphoinositol 3-kinase pathway. With this background, as preliminary, 4a-l are resolute to be potential leads, designated from their effective phosphoinositol 3-kinase (PI3-Kinase) inhibition potentials, best-docked scores, comparative ligand efficiency, and significant structural attributes evaluated by ab initio simulations...
September 12, 2018: Bioorganic Chemistry
Martin Audet, Raymond C Stevens
The first crystal structure of a G Protein-Coupled Receptor (GPCR) was that of the bovine rhodopsin, solved in 2000, and is a light receptor within retina rode cells that enables vision by transducing a conformational signal from the light-induced isomerization of retinal covalently bound to the receptor. More than seven years after this initial discovery and following more than twenty years of technological developments in GPCR expression, stabilization, and crystallography, the high-resolution structure of the adrenaline binding β2 -adrenergic receptor, a ligand diffusible receptor, was discovered...
September 21, 2018: Protein Science: a Publication of the Protein Society
Xiaojing Cong, Jérôme Golebiowski
G protein-coupled receptors (GPCRs) control most cellular communications with the environment and are the largest protein family of drug targets. As strictly regulated molecular machines, profound comprehension of their activation mechanism is expected to significantly facilitate structure-based drug design. This study provides atomistic-level description of the activation dynamics of the C-X-C chemokine receptor type 4 (CXCR4), a class A GPCR and important drug target. Using molecular dynamics and enhanced sampling, we demonstrate how mutations and protonation of conserved residues trigger activation through microswitches at the receptor core, while sodium ion - a known allosteric modulator - inhibits it...
October 3, 2018: Physical Chemistry Chemical Physics: PCCP
Thomas Günther, Giovanni Tulipano, Pascal Dournaud, Corinne Bousquet, Zsolt Csaba, Hans-Jürgen Kreienkamp, Amelie Lupp, Márta Korbonits, Justo P Castaño, Hans-Jürgen Wester, Michael Culler, Shlomo Melmed, Stefan Schulz
Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein-coupled receptors (GPCRs) called somatostatin receptor (SST)1-5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors...
October 2018: Pharmacological Reviews
Lei Wang, Dandan Yao, R N V Krishna Deepak, Heng Liu, Qingpin Xiao, Hao Fan, Weimin Gong, Zhiyi Wei, Cheng Zhang
The signaling of prostaglandin D2 (PGD2 ) through G-protein-coupled receptor (GPCR) CRTH2 is a major pathway in type 2 inflammation. Compelling evidence suggests the therapeutic benefits of blocking CRTH2 signaling in many inflammatory disorders. Currently, a number of CRTH2 antagonists are under clinical investigation, and one compound, fevipiprant, has advanced to phase 3 clinical trials for asthma. Here, we present the crystal structures of human CRTH2 with two antagonists, fevipiprant and CAY10471. The structures, together with docking and ligand-binding data, reveal a semi-occluded pocket covered by a well-structured amino terminus and different binding modes of chemically diverse CRTH2 antagonists...
October 4, 2018: Molecular Cell
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