Comparative Sequence and Structural Analyses of G-Protein-Coupled Receptor Crystal Structures and Implications for Molecular Models

Worth, Catherine L.; Kleinau, Gunnar; Krause, Gerd

doi:10.1371/journal.pone.0007011

Cited by 72 publications

(82 citation statements)

References 83 publications

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“…The results reported here are comparable to those from other similar works [19][20][21][22] which showed that GPCR modeling [23][24][25][26][27][28][29][30][31] in the absence of a crystal structure can be a valid replacement [32][33][34][35][36][37][38][39] for structural and functional exploration of GPCR receptors, and for the discovery [21,[40][41][42][43], VS [44][45][46][47][48][49][50][51][52] and optimisation [23,53] of their ligands.…”

Section: Introductionsupporting

confidence: 90%

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

Àlex¹,

Heifetz²,

Mazanetz³

et al. 2013

Med chem

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G-Protein Coupled Receptors (GPCRs) have enormous physiological and biomedical importance, being the primary target of a large number of modern drugs. The availability of structural information of the binding site of the targeted GPCR plays a key role in rationalization, efficiency and cost-effectiveness of the drug discovery process. However, obtaining structural information on GPCRs using X-ray crystallography or NMR requires a large investment of time and is technically very challenging. This situation significantly limits the ability of these methods to have an impact in drug discovery for GPCR targets in the short term and hence there is an urgent need for other effective and cost-efficient alternatives. We present here a practical approach that integrates GPCR modelling with fragment based screening to provide structural insights on the H3 and H4 histamine receptor binding sites. This approach creates a cost-efficient new avenue for structure-based drug design (SBDD) against GPCR targets. We report here a success of using this protocol for the discovery of selective and dual H3 and H4 antagonists. Our fragment screen yielded 44 H3, 21 H4 selective and 20 dual fragment hits. These fragments were used to construct high-quality H3 and H4 models followed by binding site exploration and structure based virtual screening (VS). Overall, 172 compounds were purchased for testing based on the virtual screening results. Of the 74 compounds predicted to have dual activity, 33 had activity against one or other of the two receptors (44%), of which 17 had activity against both. Of the 19 compounds predicted to be H3 selective, 13 were active against H3 (68%) and 10 of these also had selectivity over H4. Of the 79 compounds predicted to be H4 selective, 36 were active against H4 (45%) and 2 of these also had selectivity over H3.

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Section: Introductionsupporting

confidence: 90%

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

Àlex¹,

Heifetz²,

Mazanetz³

et al. 2013

Med chem

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“…Helical distortion and helix extension A number of helical features differentiate TMHs in the known structures (Worth et al 2009), including helix extensions (e.g., TMH5 and TMH6 in squid rhodopsin), Pro kink or distortion in TMH4, TMH5, TMH6, and TMH7 of most structures, Gly-Gly bulge/distortion (e.g., TMH2 of human or TMH1 of squid rhodopsins), and Gly bend (e.g., TMH3 of human rhodopsin). Some patterns of Pro in the TMH sequence lead to an insertion in the TMHs.…”

Section: Unger and Schertler 1995mentioning

confidence: 99%

“…Worth et al (2009) answered this question by analyzing in detail the sequence motifs and structural features that exist in the known structures and subsequently designing a flow diagram that allows modelers to chose the most relevant template structure, given the specific attributes observed in the query GPCR sequence. Another study has shown that using multiple templates to build a model slightly improves the resulting model (Mobarec et al 2009).…”

Section: Homology 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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“…Although the sequence similarity of these receptors is rather low (6), there are a few highly conserved residues in every transmembrane domain (TMD), and the three-dimensional arrangement of the TMDs is highly similar in all available crystal structures. These characteristics coupled with results from studies on conformational changes that occur during activation of different family A GPCRs suggest that they may share common activation mechanisms (7)(8)(9).…”

mentioning

confidence: 99%

Critical Hydrogen Bond Formation for Activation of the Angiotensin II Type 1 Receptor

Cabana

Holleran

Beaulieu

et al. 2013

Journal of Biological Chemistry

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Background:The N111G and N111W mutations make the AT 1 receptor constitutively active and inactivable, respectively. Results: The orientation and interactions of D74 2.50 are influenced by the residue at position 111 3.35 . Conclusion: H-bond formation between D742.50 and N46 1.50 is critical for AT 1 receptor activation. Significance: This novel molecular switch could be involved in the GPCR activation mechanism as it involves highly conserved residues D 2.50 and N 1.50 .

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Comparative Sequence and Structural Analyses of G-Protein-Coupled Receptor Crystal Structures and Implications for Molecular Models

Cited by 72 publications

References 83 publications

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

Modeling of mammalian olfactory receptors and docking of odorants

Critical Hydrogen Bond Formation for Activation of the Angiotensin II Type 1 Receptor

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