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

Pardo, Leonardo; Deupí, Xavier; Dölker, Nicole; López-Rodrı́guez, Marı́a L.; Campillo, Mercedes

doi:10.1002/cbic.200600429

Cited by 116 publications

(101 citation statements)

References 55 publications

(83 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In this case, the similar retinal release pattern to WT suggests that the retinal trapping found in the N55K mutant may be a distinctive feature of this form of sector RP. Our molecular modeling results suggest that the Lys residue interferes in the network between TM1, -2, and -7, due to the proximity of Asn-55, Asp-83, and Asn-302, including water molecules (44). Additionally, Fourier-transform infrared difference spectra experiments indicated that Asp-83 2.50 should be protonated (52), which would be affected by the introduction of Lys in this environment.…”

Section: Discussionmentioning

confidence: 78%

See 1 more Smart Citation

Differential Light-induced Responses in Sectorial Inherited Retinal Degeneration

Ramon

Cordomí

Aguilà

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:Two new rhodopsin mutations associated with the rare form sector retinitis pigmentosa (RP) have been found. Results: Characterization of both rhodopsin mutant proteins shows different progression correlating with a different behavior of rhodopsin upon light exposure. Conclusion: Light plays an important role in triggering sector RP. Significance: Other mechanisms, in addition to protein misfolding, underlie GPCR dysfunction in pathological processes.

show abstract

Section: Discussionmentioning

confidence: 78%

“…3C) (44). In the N55K substitution, the Lys side chain would interfere with these contacts and form a salt bridge with Asp-83 2.50 .…”

Section: Resultsmentioning

confidence: 99%

Differential Light-induced Responses in Sectorial Inherited Retinal Degeneration

Ramon

Cordomí

Aguilà

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Nevertheless, comparison of the structure of inactive rhodopsin (Li et al, 2004) with the crystal structure of the ligand-free opsin (Park et al, 2008) has provided additional insights into these processes. Specifically, we propose that the Thr3.36/ Trp6.48 rotamer toggle switch disrupts a conserved hydrogen bond network linking Trp6.48 and Asp2.50 (Li et al, 2004;Pardo et al, 2007;Rosenbaum et al, 2007), triggering the conformational transition of Asn7.49 toward Asp2.50 (Urizar et al, 2005) and ultimately leading to the extended conformation, pointing toward the protein core, of Arg3.50 (Park et al, 2008). On the other hand, the agonist-induced inward movement of the extracellular part of TM6 toward TM3 (Schwartz et al, 2006) might cause the intracellular movement of TM6 toward TM5, facilitating the observed ionic interaction between Glu6.30 and Lys5.66 (Park et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Conformational Toggle Switches Implicated in Basal Constitutive and Agonist-Induced Activated States of 5-Hydroxytryptamine-4 Receptors

Pellissier¹,

Sallander²,

Campillo³

et al. 2009

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

The extended classic ternary complex model predicts that a G protein-coupled receptor (GPCR) exists in only two interconvertible states: an inactive R, and an active R*. However, different structural active R* complexes may exist in addition to a silent inactive R ground state (Rg). Here we demonstrate, in a cellular context, that several R* states of 5-hydroxytryptamine-4 (5-HT 4 ) receptors involve different side-chain conformational toggle switches. Using site-directed mutagenesis and molecular modeling approaches, we show that the basal constitutive receptor (R*basal) results from stabilization of an obligatory double toggle switch (Thr3.36 from inactive gϪ to active gϩ and Trp6.48 from inactive gϩ to active t

show abstract

“…46) It has been proposed that hydrophilic residues may play a role in the structure changes involved in GPCRs activation. 47) Based on simulations in the a 1B adrenergic receptor, Scheer et al 48) suggested that the Arg131 in the inactive state is constrained in a "polar pocket" formed by residues in TMH I, II, and VII. Upon mutation of the adjacent Asp130 the arginine shifts out of the polar pocket leading to long range conformational changes.…”

Section: Discussionmentioning

confidence: 99%

Mutation of Important Amino Acid Residue of Asp104Lys in Human .BETA.1-Adrenergic Receptor Triggers Functional and Constitutive Inactivation

Hossain

Ahmed

Bhuiyan

et al. 2008

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

The b 1 -adrenergic receptor (b 1 -AR) belongs to the largest super family of G-protein-coupled receptors (GPCRs). The b 1 -AR responds to norepinephrine and epinephrine by activating adenylyl cyclase pathway and promotes production of cAMP.1) Activation of cardiac b-adrenergic receptors plays an important role in regulating the physiological responses of the heart to an increase demand.2) The pathophysiology of human b 1 -ARs is associated with several cardiovascular diseases such as dilated cardiomyopathy, congestive heart failure, ventricular arrhythmia and sudden death. [3][4][5] Recently, several GPCRs have exhibited constitutive activity and inactivity in vivo. Naturally occurring amino acid mutations in the luteinizing hormone receptor, 6) parathyroid hormone receptor, 7) melanocyte-stimulating hormone receptor, 8) thyrotropin receptor 9) and rhodopsin receptor 10) result in constitutive activation of second messenger production and are thought to play a role in disease pathophysiology. Constitutively active mutant receptors have been a valuable tool to demonstrate that certain ligands stabilize inactive conformations. Those ligands are known as inverse agonist, given that they have the opposite effect of agonists. Therefore, b-antagonists are used clinically to reduce heart rate and force of contraction in hypertension, angina and acute myocardial infarction by direct blocking endogenous catecholamine activity, [11][12][13] implying that inverse agonists may have preferred therapeutic applications in the pathophysiology of several cardiovascular diseases.In all seven transmembrane helix (TMH) of GPCRs it appears that the general mechanism of activation involves disruption of intramolecular constraints, leading to TMH movement and formation of new interactions, which stabilize the active state of the receptor. [14][15][16][17][18][19][20][21][22][23][24][25][26][27] The aspartic acid at position 104 in TMH II of the human b 1 -AR is conserved in all b-adrenergic 28-31) , a-adrenergic receptor 32) and also muscarinic cholinergic receptors, [33][34][35] which may take part in an ionic interaction with amino group containing catecholamines, whose disruption of interaction makes the receptor active conformation state. It was reported by Chung et al. 36) that aspartic acid residue at position 79 in putative TMH II of b 2 -AR was involved in agonist binding and receptor activation. Substitution of aspartic acid to alanine and asparagine at position 79 did not affect the antagonist binding but significantly decreased the binding affinity of agonists. 37)Moreover, this mutant receptor also affected the functional activity compared to wild type receptor by uncoupling with GPCRs.With the help of molecular modeling, we previously identified the important binding sites of b 1 -AR. We showed that Asp104 in TMH II of b 1 -AR makes strong electrostatic interaction with functional groups of SWR-0342SA.38) Through mutagenesis studies, we suggested that Asp104 is very important site for the ligand binding and functional...

show abstract

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

Cited by 116 publications

References 55 publications

Differential Light-induced Responses in Sectorial Inherited Retinal Degeneration

Differential Light-induced Responses in Sectorial Inherited Retinal Degeneration

Conformational Toggle Switches Implicated in Basal Constitutive and Agonist-Induced Activated States of 5-Hydroxytryptamine-4 Receptors

Mutation of Important Amino Acid Residue of Asp104Lys in Human .BETA.1-Adrenergic Receptor Triggers Functional and Constitutive Inactivation

Contact Info

Product

Resources

About