Integral polytopic membrane proteins contain only two types of folds in their transmembrane domains: α-helix bundles and β-barrels. The increasing number of available crystal structures of these ...proteins permits an initial estimation of how sequence variability affects the structure conservation in their transmembrane domains. We, thus, aim to determine the pairwise sequence identity necessary to maintain the transmembrane molecular architectures compatible with the hydrophobic nature of the lipid bilayer.
Root-mean-square deviation (rmsd) and sequence identity were calculated from the structural alignments of pairs of homologous polytopic membrane proteins sharing the same fold. Analysis of these data reveals that transmembrane segment pairs with sequence identity in the so-called 'twilight zone' (20-35%) display high-structural similarity (rmsd < 1.5 Å). Moreover, a large group of β-barrel pairs with low-sequence identity (<20%) still maintain a close structural similarity (rmsd < 2.5 Å). Thus, we conclude that fold preservation in transmembrane regions requires less sequence conservation than for globular proteins. These findings have direct implications in homology modeling of evolutionary-related membrane proteins.
Supplementary data are available at Bioinformatics online.
GPCRmd uncovers the dynamics of the 3D-GPCRome Rodríguez-Espigares, Ismael; Torrens-Fontanals, Mariona; Tiemann, Johanna K S ...
Nature methods,
08/2020, Letnik:
17, Številka:
8
Journal Article
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G-protein-coupled receptors (GPCRs) are involved in numerous physiological processes and are the most frequent targets of approved drugs. The explosion in the number of new three-dimensional (3D) ...molecular structures of GPCRs (3D-GPCRome) over the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this protein family. Molecular dynamics (MD) simulations have become a widely established technique for exploring the conformational landscape of proteins at an atomic level. However, the analysis and visualization of MD simulations require efficient storage resources and specialized software. Here we present GPCRmd (http://gpcrmd.org/), an online platform that incorporates web-based visualization capabilities as well as a comprehensive and user-friendly analysis toolbox that allows scientists from different disciplines to visualize, analyze and share GPCR MD data. GPCRmd originates from a community-driven effort to create an open, interactive and standardized database of GPCR MD simulations.
The interactions of Met and Cys with other amino acid side chains have received little attention, in contrast to aromatic–aromatic, aromatic–aliphatic or/and aliphatic–aliphatic interactions. ...Precisely, these are the only amino acids that contain a sulfur atom, which is highly polarizable and, thus, likely to participate in strong Van der Waals interactions. Analysis of the interactions present in membrane protein crystal structures, together with the characterization of their strength in small‐molecule model systems at the ab‐initio level, predicts that Met–Met interactions are stronger than Met–Cys ≈ Met–Phe ≈ Cys–Phe interactions, stronger than Phe–Phe ≈ Phe–Leu interactions, stronger than the Met–Leu interaction, and stronger than Leu–Leu ≈ Cys–Leu interactions. These results show that sulfur‐containing amino acids form stronger interactions than aromatic or aliphatic amino acids. Thus, these amino acids may provide additional driving forces for maintaining the 3D structure of membrane proteins and may provide functional specificity.
The clinical spectrum of
-related neurodevelopmental disorders (GRD) results from gene- and variant-dependent primary alterations of the NMDA receptor, disturbing glutamatergic neurotransmission. ...Despite
gene variants' functional annotations being dually critical for stratification and precision medicine design, genetically diagnosed pathogenic
variants currently outnumber their relative functional annotations. Based on high-resolution crystal 3D models and topological domains conservation between GluN1, GluN2A, and GluN2B subunits of the NMDAR, we have generated GluN1-GluN2A-GluN2B subunits structural superimposition model to find equivalent positions between GluN subunits. We have developed a
structural algorithm that predicts functional changes in the equivalent structural positions in other GluN subunits. GRIN structural algorithm was computationally evaluated to the full
missense variants repertoire, consisting of 4,525 variants. The analysis of this structure-based model revealed an absolute predictive power for GluN1, GluN2A, and GluN2B subunits, both in terms of pathogenicity-association (benign vs. pathogenic variants) and functional impact (loss-of-function, benign, gain-of-function). Further, we validated this computational algorithm experimentally, using an
library of GluN2B-equivalent GluN2A artificial variants, designed from pathogenic GluN2B variants. Thus, the implementation of the GRIN structural algorithm allows to computationally predict the pathogenicity and functional annotations of
variants, resulting in the duplication of pathogenic
variants assignment, reduction by 30% of
variants with uncertain significance, and increase by 70% of functionally annotated
variants. Finally, GRIN structural algorithm has been implemented into
variants Database (http://lmc.uab.es/grindb), providing a computational tool that accelerates
missense variants stratification, contributing to clinical therapeutic decisions for this neurodevelopmental disorder.
The contribution of the HLA-E/NKG2X axis in NK-mediated control of HIV infection remains unclear. We have studied the relationship between HLA-E expression and phenotypical as well as functional ...characteristics of NK cells, in the context of chronic HIV infection and in an
model of acute infection. High viremia in HIV+ individuals was related to increased HLA-E expression, and changes in NK subpopulations, especially a reduction of the CD56
as well as an increase in adaptive NK subpopulation. Uncontrolled HIV infection was also characterized by a reversion of the NKG2A/NKG2C expression ratio and a loss of positive and negative regulation of NK mediated by HLA-E. This was reflected in a lower cytotoxic, degranulation and cytokine production capacity, especially in CD56
and adaptive NK. In line with these results, HLA-E expression showed a positive correlation with viral growth inhibition in an
model of acute infection at day 7, which was lost after 14 days of culture. Using HLA-E expressing K562 cells, we determined that only one out of 11 described HIV-derived HLA-E epitopes increased HLA-E surface stability. In spite of that, eight of the 11 epitopes were capable of increasing degranulation and three drove differences in NK-cell mediated cell lysis or cytokine secretion. In conclusion, our results indicate that HLA-E molecules presenting HIV-derived epitopes may sensitize target cells for NK lysis in early HIV infection. However, prolonged exposure to elevated HLA-E expression levels
may lead to NK cell dysfunction and reduced viral control In chronic infection.
The role of Cysteine 6.47 in class A GPCRs Olivella, Mireia; Caltabiano, Gianluigi; Cordomí, Arnau
BMC structural biology,
03/2013, Letnik:
13, Številka:
1
Journal Article
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The CWxP motif of transmembrane helix 6 (x: any residue) is highly conserved in class A GPCRs. Within this motif, W6.48 is a big star in the theory of the global "toggle switch" because of its key ...role in the activation mechanism of GPCRs upon ligand binding. With all footlights focused on W6.48, the reason why the preceding residue, C6.47, is largely conserved is still unknown. The present study is aimed to fill up this lack of knowledge by characterizing the role of C6.47 of the CWxP motif.
A complete analysis of available crystal structures has been made alongside with molecular dynamics simulations of model peptides to explore a possible structural role for C6.47.
We conclude that C6.47 does not modulate the conformation of the TM6 proline kink and propose that C6.47 participates in the rearrangement of the TM6 and TM7 interface accompanying activation.
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