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7×7 RMSD matrix: A new method for quantitative comparison of the transmembrane domain structures in the G-protein coupled receptors.

ABSTRACT: The G-protein coupled receptors (GPCRs) share a conserved heptahelical fold in the transmembrane (TM) region, but the exact arrangements of the seven TM helices vary with receptors and their activation states. The differences or the changes have been observed in the experimentally solved structures, but have not been systematically and quantitatively investigated due to lack of suitable methods. In this work, we describe a novel method, called 7×7 RMSD matrix that is proposed specifically for comparing the characteristic 7TM bundle structures of GPCRs. Compared to the commonly used overall TM bundle RMSD as a single parameter, a 7×7 RMSD matrix contains 49 parameters, which reveal changes of the relative orientations of the seven TMs. We demonstrate the novelty and advantages of this method by tackling two problems that are challenging for the existing methods. With this method, we are able to identify and quantify the helix movements in the activated receptor structures and reveal structural conservation and divergence as well as the structural relationships of different GPCRs in terms of the relative orientations of the seven TMs.

SUBMITTER: Wang T

PROVIDER: S-EPMC5522649 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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7×7 RMSD matrix: A new method for quantitative comparison of the transmembrane domain structures in the G-protein coupled receptors.

Wang Ting T Wang Yang Y Tang Leihan L Duan Yong Y Liu Haiguang H

Journal of structural biology 20170220 2

The G-protein coupled receptors (GPCRs) share a conserved heptahelical fold in the transmembrane (TM) region, but the exact arrangements of the seven TM helices vary with receptors and their activation states. The differences or the changes have been observed in the experimentally solved structures, but have not been systematically and quantitatively investigated due to lack of suitable methods. In this work, we describe a novel method, called 7×7 RMSD matrix that is proposed specifically for co ...[more]

PMID: 28223044

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Project description:BACKGROUND:The accuracy of any 3D-QSAR, Pharmacophore and 3D-similarity based chemometric target fishing models are highly dependent on a reasonable sample of active conformations. Since a number of diverse conformational sampling algorithm exist, which exhaustively generate enough conformers, however model building methods relies on explicit number of common conformers. RESULTS:In this work, we have attempted to make clustering algorithms, which could find reasonable number of representative conformer ensembles automatically with asymmetric dissimilarity matrix generated from openeye tool kit. RMSD was the important descriptor (variable) of each column of the N × N matrix considered as N variables describing the relationship (network) between the conformer (in a row) and the other N conformers. This approach used to evaluate the performance of the well-known clustering algorithms by comparison in terms of generating representative conformer ensembles and test them over different matrix transformation functions considering the stability. In the network, the representative conformer group could be resampled for four kinds of algorithms with implicit parameters. The directed dissimilarity matrix becomes the only input to the clustering algorithms. CONCLUSIONS:Dunn index, Davies-Bouldin index, Eta-squared values and omega-squared values were used to evaluate the clustering algorithms with respect to the compactness and the explanatory power. The evaluation includes the reduction (abstraction) rate of the data, correlation between the sizes of the population and the samples, the computational complexity and the memory usage as well. Every algorithm could find representative conformers automatically without any user intervention, and they reduced the data to 14-19% of the original values within 1.13 s per sample at the most. The clustering methods are simple and practical as they are fast and do not ask for any explicit parameters. RCDTC presented the maximum Dunn and omega-squared values of the four algorithms in addition to consistent reduction rate between the population size and the sample size. The performance of the clustering algorithms was consistent over different transformation functions. Moreover, the clustering method can also be applied to molecular dynamics sampling simulation results.

Project description:UnlabelledCoevolution of herpesviruses with their respective host has resulted in a delicate balance between virus-encoded immune evasion mechanisms and host antiviral immunity. BILF1 encoded by human Epstein-Barr virus (EBV) is a 7-transmembrane (7TM) G-protein-coupled receptor (GPCR) with multiple immunomodulatory functions, including attenuation of PKR phosphorylation, activation of G-protein signaling, and downregulation of major histocompatibility complex (MHC) class I surface expression. In this study, we explored the evolutionary and functional relationships between BILF1 receptor family members from EBV and 12 previously uncharacterized nonhuman primate (NHP) lymphocryptoviruses (LCVs). Phylogenetic analysis defined 3 BILF1 clades, corresponding to LCVs of New World monkeys (clade A) or Old World monkeys and great apes (clades B and C). Common functional properties were suggested by a high degree of sequence conservation in functionally important regions of the BILF1 molecules. A subset of BILF1 receptors from EBV and LCVs from NHPs (chimpanzee, orangutan, marmoset, and siamang) were selected for multifunctional analysis. All receptors exhibited constitutive signaling activity via G protein Gαi and induced activation of the NF-κB transcription factor. In contrast, only 3 of 5 were able to activate NFAT (nuclear factor of activated T cells); chimpanzee and orangutan BILF1 molecules were unable to activate NFAT. Similarly, although all receptors were internalized, BILF1 from the chimpanzee and orangutan displayed an altered cellular localization pattern with predominant cell surface expression. This study shows how biochemical characterization of functionally important orthologous viral proteins can be used to complement phylogenetic analysis to provide further insight into diverse microbial evolutionary relationships and immune evasion function.ImportanceEpstein-Barr virus (EBV), known as an oncovirus, is the only human herpesvirus in the genus Lymphocryptovirus (LCV). EBV uses multiple strategies to hijack infected host cells, establish persistent infection in B cells, and evade antiviral immune responses. As part of EBV's immune evasion strategy, the virus encodes a multifunctional 7-transmembrane (7TM) G-protein-coupled receptor (GPCR), EBV BILF1. In addition to multiple immune evasion-associated functions, EBV BILF1 has transforming properties, which are linked to its high constitutive activity. We identified BILF1 receptor orthologues in 12 previously uncharacterized LCVs from nonhuman primates (NHPs) of Old and New World origin. As 7TM receptors are excellent drug targets, our unique insight into the molecular mechanism of action of the BILF1 family and into the evolution of primate LCVs may enable validation of EBV BILF1 as a drug target for EBV-mediated diseases, as well as facilitating the design of drugs targeting EBV BILF1.

Dataset Information

7×7 RMSD matrix: A new method for quantitative comparison of the transmembrane domain structures in the G-protein coupled receptors.

Publications

7×7 RMSD matrix: A new method for quantitative comparison of the transmembrane domain structures in the G-protein coupled receptors.

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