The Role of Internal Water Molecules in the Structure and Function of the Rhodopsin Family of G Protein‐Coupled Receptors

Pardo, Leonardo; Deupí, Xavier; Doelker, Nicole; López-Rodrı́guez, Marı́a L.; Campillo, M.

doi:10.1002/chin.200714261

Cited by 26 publications

(50 citation statements)

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“…To demonstrate the utility of the meta-analysis tool, and due to their critical role in receptor function 31,30,32 , we investigated the interaction fingerprint of water molecules in GPCRs. Along with previously described 33 conserved water networks , this analysis revealed other water-mediated interactions that are conserved among different receptor subtypes and firstly reported here.…”

Section: Functional Hotspots Discovered Through Meta-analysis Of Gpcrmentioning

confidence: 99%

GPCRmd uncovers the dynamics of the 3D-GPCRome

Rodríguez‐Espigares

Torrens‐Fontanals

Tiemann

et al. 2019

Preprint

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G protein-coupled receptors (GPCRs) are involved in numerous physiological processes and the most frequent targets of approved drugs. The striking explosion in the number of new 3D molecular structures of GPCRs (3D-GPCRome) during the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this protein family. While experimentally-resolved structures undoubtedly provide valuable snapshots of specific GPCR conformational states, they give only limited information on their flexibility and dynamics associated with function.Molecular dynamics (MD) simulations have become a widely established technique to explore the conformational landscape of proteins at an atomic level. However, the analysis and visualization of MD simulations requires efficient storage resources and specialized software, hence limiting the dissemination of these data to specialists in the field. Here we present the GPCRmd, an online platform with web-based visualization capabilities and a comprehensive analysis toolbox that allows scientists from any discipline to visualize, share, and analyse GPCR MD data. We describe the GPCRmd in the context of a community-driven effort to create the first open, interactive, and standardized database of GPCR MD simulations. We demonstrate the power of this resource by performing comparative analyses of multiple GPCR simulations on two mechanisms critical to receptor function: internal water networks and sodium ion interaction.

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Section: Functional Hotspots Discovered Through Meta-analysis Of Gpcrmentioning

confidence: 99%

GPCRmd uncovers the dynamics of the 3D-GPCRome

Rodríguez‐Espigares

Torrens‐Fontanals

Tiemann

et al. 2019

Preprint

Self Cite

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“…D83 (2.50) has an important role in Meta II formation; mutations in this amino acid affect such an equilibrium and the D83 environment changes during the photoactivation process [37,39]. This amino acid interacts with the NPxxY motif, in helix 7, through a cluster of water molecules and forms a hydrogen bond with the neighbouring N55 (1.50) [39][40][41]. The crystal structure of opsin bound to Gt shown in Fig.…”

Section: Rhodopsinmentioning

confidence: 99%

Alterations in the photoactivation pathway of rhodopsin mutants associated with retinitis pigmentosa

et al. 2011

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The visual photoreceptor rhodopsin undergoes a series of conformational changes upon light activation, eventually leading to the active metarhodopsin II conformation, which is able to bind and activate the G‐protein, transducin. We have previously shown that mutant rhodopsins G51V and G89D, associated with retinitis pigmentosa, present photobleaching patterns characterized by the formation of altered photointermediates whose nature remained obscure. Our current detailed UV–visible spectroscopic analysis, together with functional characterization, indicate that these mutations influence the relative stability of the different metarhodopsin photointermediates by altering their equilibria and maintaining the receptor in a nonfunctional light‐induced conformation that may be toxic to photoreceptor cells. We propose that G51V and G89D shift the equilibrium from metarhodopsin I towards an intermediate, recently named as metarhodopsin Ib, proposed to interact with transducin without activating it. This may be one of the causes contributing to the molecular mechanisms underlying cell death associated with some retinitis pigmentosa mutations.

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“…However, substitution of the hydrophobic residue Trp29 with the polar Cys residue is likely to affect the insertion or stability of TM1 in the cell membrane. In other homologous class A GPCRs, TM1 contributes hydrogen bonds to stabilize a critical interhelical association with TM7, which is necessary for receptor structural integrity and helps to define the ligandbinding site in the inactive receptor state [18,26]. In keeping with this critical role for TM1, variant TP receptors with substituted TM1 residues showed reduced ligandbinding affinity as compared with the WT receptor [8].…”

Section: Discussionmentioning

confidence: 98%