An Overview on GPCRs and Drug Discovery: Structure-Based Drug Design and Structural Biology on GPCRs

Lundström, Kenneth

doi:10.1007/978-1-60327-317-6_4

Cited by 122 publications

(85 citation statements)

References 91 publications

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“…In addition to their key role in major signaling pathways, such as sensing (e.g., smell, light, hormones or neurotransmitters), numerous drugs and toxins also act through GPCR proteins. Regulation of blood plasma calcium levels and water reabsorption in the kidney are both achieved by the functioning of specific GPCRs [8,9].…”

Section: Role Of Membrane Proteins In Health Disease and Medical Diagnmentioning

confidence: 99%

Cell Surface Membrane Proteins as Personalized Biomarkers: Where we Stand and Where we are Headed

et al. 2013

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Personalized medicine requires the development of a wide array of biomarker diagnostic assays, reflecting individual variations and thus allowing tailored therapeutic interventions. Membrane proteins comprise approximately 30% of total human proteins; they play a key role in various physiological functions and pathological conditions, although, currently, only a limited number of membrane proteins are applied as biomarkers. In many normal tissues, cell surface membrane proteins are not easily accessible for diagnostic sampling, and tumor-derived membrane preparations – while serving as potential tumor biomarkers – may not reflect physiological protein expression. In addition to post-translational modifications, which may include glycosylation, phosphorylation and lipid modifications, the trafficking of membrane proteins is also regulated. Moreover, a tight cellular quality control monitors membrane protein maturation, and continuous removal and reinsertion, involving special signaling systems, occurs in many cases. However, cell surface membrane proteins already serve as valuable prognostic and predicative biomarkers, for example, in hematological and immunological diseases, by the determination of the cluster of differentiation markers. In this review, we demonstrate the relevance of cell surface membrane biomarkers in various diseases and call attention to the potential application of red blood cell (erythrocyte) membrane proteins in this regard. Surprisingly, red blood cells express hundreds of membrane proteins, which seem to reflect a general genetic and regulatory background, and may serve as relatively stable and easily accessible personalized membrane biomarkers. Quantitative membrane protein detection in red blood cells by flow cytometry may bring a breakthrough in this regard.

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Section: Role Of Membrane Proteins In Health Disease and Medical Diagnmentioning

confidence: 99%

Cell Surface Membrane Proteins as Personalized Biomarkers: Where we Stand and Where we are Headed

et al. 2013

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“…GPCRs serve as gatekeepers, modulating numerous intracellular signaling cascades in response to a wide variety of extracellular stimuli including peptides, proteins, amino acids, lipids, nucleotides, photons and neurotransmitters. Corresponding to their physiological import, GPCRs are the targets of 50-60% of currently marketed drugs (Lundstrom 2009). Elucidating the structure of GPCRs is key both in terms of understanding this important class of proteins and because of the indispensable role this may play in the field of drug discovery (Allen and Roth 2011).…”

Section: Introductionmentioning

confidence: 99%

Small expression tags enhance bacterial expression of the first three transmembrane segments of the apelin receptor

Pandey

Sarker

Liu

et al. 2014

Biochem. Cell Biol.

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G-protein coupled receptors (GPCRs) are inherently dynamic membrane protein modulators of various important cellular signaling cascades. The apelin receptor (AR or APJ) is a class A GPCR involved in numerous physiological processes, implicated in angiogenesis during tumour formation and as a CD4 co-receptor for entry of human immunodeficiency virus type 1 (HIV-1) to cells. Due to the lack of efficient methods to produce full-length GPCRs enriched with nuclear magnetic resonance (NMR) active 15 N, 13 C and/or 2 H isotopes, small GPCR fragments typically comprising 1-2 transmembrane segments are frequently studied using NMR spectroscopy. Here, we report successful overexpression of transmembrane segments 1-3 of AR (AR_TM1-3) in the C41(DE3) strain of Escherichia coli using an AT-rich gene tag previously reported to enhance cellfree expression yields. The resulting protein, with 6 additional N-terminal residues due to the expression tag, was purified using high performance liquid chromatography (HPLC). Farultraviolet circular dichroism spectropolarimetry demonstrates that AR_TM1-3 has the predicted ~40% α-helical character in membrane-mimetic environments. 1 H-15 N HSQC NMR experiments imply amenability to high-resolution NMR structural characterization and stability in solution for weeks. Notably, this small expression tag approach may also be generally applicable to other membrane proteins that are difficult to express in E. coli.

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“…The GPCR superfamily is the largest group of cell surface receptors with more than 800 members (1). Dysfunction of GPCRs leads to many prevalent human diseases, and these proteins represent a common therapeutic potential with 50 -60% of all drugs targeting these receptors (2). Downstream signaling targets of GPCR activation are also key enzymes for drug development; one of those is phospholipase D (PLD).…”

mentioning

confidence: 99%

Regulation of Phospholipase D Activity and Phosphatidic Acid Production after Purinergic (P2Y6) Receptor Stimulation

Scott¹,

Xiang²,

Mathews³

et al. 2013

Journal of Biological Chemistry

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Background: Phosphatidic acid is a key lipid second messenger often generated after receptor stimulation. Results: After P2Y 6 receptor stimulation both PLD and DGK enzymes are responsible for producing PA species. Conclusion: DGK facilitates a negative regulation of PLD and tightly controls PA levels. Significance: Further understanding the PA signaling network is critical to developing next generation therapeutics for human diseases.

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An Overview on GPCRs and Drug Discovery: Structure-Based Drug Design and Structural Biology on GPCRs

Cited by 122 publications

References 91 publications

Cell Surface Membrane Proteins as Personalized Biomarkers: Where we Stand and Where we are Headed

Cell Surface Membrane Proteins as Personalized Biomarkers: Where we Stand and Where we are Headed

Small expression tags enhance bacterial expression of the first three transmembrane segments of the apelin receptor

Regulation of Phospholipase D Activity and Phosphatidic Acid Production after Purinergic (P2Y6) Receptor Stimulation

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