I want a new drug: G-protein-coupled receptors in drug development

Schlyer, Sabine; Horuk, Richard

doi:10.1016/j.drudis.2006.04.008

Cited by 200 publications

(130 citation statements)

References 84 publications

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“…Eventually, the new structure (Costanzi 2008). With the availability of high-resolution GPCR structures, it became possible to combine traditional homology modeling techniques with ligandbased pharmacophore modeling (Mobarec and Filizola 2008;Schlyer and Horuk 2006).…”

Section: Gpcr 3d Structure Modelingmentioning

confidence: 99%

Modeling of mammalian olfactory receptors and docking of odorants

et al. 2012

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Olfactory receptors (ORs) belong to the superfamily of G protein-coupled receptors (GPCRs), the second largest class of genes after those related to immunity, and account for about 3 % of mammalian genomes. ORs are present in all multicellular organisms and represent more than half the GPCRs in mammalian species (e.g., the mouse OR repertoire contains >1,000 functional genes). ORs are mainly expressed in the olfactory epithelium where they detect odorant molecules, but they are also expressed in a number of other cells, such as sperm cells, although their functions in these cells remain mostly unknown. It has recently been reported that ORs are present in tumoral tissues where they are expressed at different levels than in healthy tissues. A specific OR is overexpressed in prostate cancer cells, and activation of this OR has been shown to inhibit the proliferation of these cells. Odorant stimulation of some of these receptors results in inhibition of cell proliferation. Even though their biological role has not yet been elucidated, these receptors might constitute new targets for diagnosis and therapeutics. It is important to understand the activation mechanism of these receptors at the molecular level, in particular to be able to predict which ligands are likely to activate a particular receptor ('deorphanization') or to design antagonists for a given receptor. In this review, we describe the in silico methodologies used to model the three-dimensional (3D) structure of ORs (in the more general framework of GPCR modeling) and to dock ligands into these 3D structures.

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Section: Gpcr 3d Structure Modelingmentioning

confidence: 99%

Modeling of mammalian olfactory receptors and docking of odorants

et al. 2012

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“…GPCRs are involved in a multitude of physiological functions and therefore have emerged as major targets for the development of novel drug candidates in all clinical areas [3]. Interestingly, it is becoming increasingly clear that GPCRs need to be viewed in the context of the membrane lipid environment surrounding them.…”

Section: Amitabha Chattopadhyaymentioning

confidence: 99%

“…012: Proteopedia-a scientific 'Wiki' bridging the rift between 3D structure and function of biomacromolecules 1,2 Joel L. Sussman, 3 Eran Hodis, Biologists and biochemists are now able to access 3D images of biomacromolecules underlying biological functions and disease. Rather than relying on text to provide the understanding of biomacromolecule structures, a collaborative website called Proteopedia now provides a new resource by linking written information and 3D structural information.…”

mentioning

confidence: 99%

HGM2008 structural proteomics symposium abstracts

2008

HUGO J

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Structural studies on proteins involved in recombination and repair, reviewed here, form a component of a larger programme, being pursued in this laboratory, on the structural biology of mycobacterial proteins. Crystallographic and related studies on RecA from M. tuberculosis and M. smegmatis have involved the wild type protein, mutants and their nucleotide complexes crystallized under different conditions. These studies provide a comprehensive picture of RecA-ATP interactions and lead to the proposal of a mechanism for the transmission of the information on nucleotide binding to the DNA binding region using a switch residue. Furthermore, the structures enable a thorough elucidation of the plasticity of the molecule resulting primarily from the movement of the C-terminal domain, which is related to the pitch of the RecA filament, several loops and the switch residue. They also provide snapshots of allosteric transitions involved in the activity cycle of RecA. Crystallographic and modeling studies of RuvA from M. tuberculosis, which plays an important role in resolving Holliday Junctions, provide a framework for understating the regional flexibility of the molecule and RuvAHolliday Junction interactions. Single stranded DNA binding protein (SSB), an essential protein necessary for replication, recombination and repair, from M. tuberculosis, M. smegmatis and M. lepre have been studied using crystallography. The quaternary structure of the tetrameric molecule from mycobacteria is different from that of SSB from other sources. This difference has important implications in relation to DNA binding and the stability of the protein. The structure of uracil-DNA glycosylase, a repair enzyme involved in excision of uracil from DNA, from M. tuberculosis has been determined in its complex with a proteinaceous inhibitor. The structural and associated modeling studies reveal the unique features of the mycobacterial enzyme. In addition to providing valuable information pertaining to the function of the concerned proteins, the structures presented here bring out the critical differences of mycobacterial proteins form the homologues from other sources. These differences could be important in determining the special features of mycobacteria and in combating the pathogens among them.

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“…About half of the drug targets in the pharmaceutical industry are GPCRs, which also, not coincidentally, comprise the largest family of cell-surface receptors [26]. GPCRs become activated by chemokines, small (8-10 kDa) soluble protein ligands that are either promiscuous or specific for a given receptor.…”

Section: Physiological Roles Of the Main Coreceptorsmentioning

confidence: 99%

Chemokine Receptors as Therapeutic Targets in HIV Infection

Anastassopoulou¹

2012

Immunodeficiency

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I want a new drug: G-protein-coupled receptors in drug development

Cited by 200 publications

References 84 publications

Modeling of mammalian olfactory receptors and docking of odorants

Modeling of mammalian olfactory receptors and docking of odorants

HGM2008 structural proteomics symposium abstracts

Chemokine Receptors as Therapeutic Targets in HIV Infection

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