Influence of the g− conformation of Ser and Thr on the structure of transmembrane helices

Deupí, Xavier; Olivella, Mireia; Sanz, Arantxa; Dölker, Nicole; Campillo, Mercedes; Pardo, Leonardo

doi:10.1016/j.jsb.2009.09.009

Cited by 27 publications

(23 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In transmembrane α-helices side chain conformations of Thr are mostly limited to gauche + 38 in which the hydroxyl group forms hydrogen bonds with the backbone carbonyl oxygen at position i-3 and the methyl group points toward L 4.56 . The methyl group of Thr forces L 4.56 to adopt the gauche + conformation pointing away from the bundle and expanding the length of the channel in S1P 5 , in contrast to the small Ala that permits L 4.56 , in the trans conformation, to pack against TM 3 making the channel shorter in S1P 4 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Ligand chain length drives activation of lipid G protein-coupled receptors

Troupiotis-Tsaïlaki

Zachmann

González-Gil

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Sphingosine-1-phosphate (S1P) is a lipid mediator that can activate five cell membrane G protein-coupled receptors (GPCRs) which carry a variety of essential functions and are promising drug targets. S1P is composed of a polar zwitterionic head-group and a hydrophobic alkyl chain. This implies an activation mechanism of its cognate receptor that must be significantly different from what is known for prototypical GPCRs (ie receptor to small hydrophilic ligands). Here we aim to identify the structural features responsible for S1P agonism by combining molecular dynamics simulations and functional assays using S1P analogs of different alkyl chain lengths. We propose that high affinity binding involves polar interactions between the lipid head-group and receptor side chains while activation is due to hydrophobic interactions between the lipid tail and residues in a distinct binding site. We observe that ligand efficacy is directly related to alkyl chain length but also varies with receptor subtypes in correlation with the size of this binding pocket. Integrating experimental and computational data, we propose an activation mechanism for the S1P receptors involving agonist-induced conformational events that are conserved throughout class A GPCRs.

show abstract

Section: Resultsmentioning

confidence: 99%

Ligand chain length drives activation of lipid G protein-coupled receptors

Troupiotis-Tsaïlaki

Zachmann

González-Gil

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although we showed that Ser217 5.44 , like Asn268 6.52 , was essential for compound 1 binding, it showed no direct interaction with compound 1 in our model. Threonine (class A orthologs) and serine (class B orthologs) residues in combination with proline residues are known to cause kinks in TM helixes (Deupi et al, 2010), as demonstrated, for example, by the T 2.56 XP 2.58 -induced kink in TM2 in chemokine receptors (Govaerts et al, 2001; Wu et al, 6.52 , interact with compound 1 (Fig. 8; Table 5).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Allosteric Binding Site in the CXCR2 Chemokine Receptor

Kruijf¹,

Lim

Roumen

et al. 2011

Mol Pharmacol

View full text Add to dashboard Cite

We have shown previously that different chemical classes of small-molecule antagonists of the human chemokine CXCR2 receptor interact with distinct binding sites of the receptor. Although an intracellular binding site for diarylurea CXCR2 antagonists, such as N-(2-bromophenyl)-NЈ-(7-cyano-1H-benzotriazol-4-yl)urea (SB265610), and thiazolopyrimidine compounds was recently mapped by mutagenesis studies, we now report on an imidazolylpyrimidine antagonist binding pocket in the transmembrane domain of CXCR2. Using different CXCR2 orthologs, chimeric proteins, site-directed mutagenesis, and in silico modeling, we have elucidated the binding mode of this antagonist. Our in silico-guided mutagenesis studies indicate that the ligand binding cavity for imidazolylpyrimidine compounds in CXCR2 is located between transmembrane (TM) helices 3 (Phe130 3.36 ), 5 (Ser217 5.44 , Phe220 5.47 ), and 6 (Asn268 6.52 , Leu271 6.55 ) and suggest that these antagonists enter CXCR2 via the TM5-TM6 interface. It is noteworthy that the same interface is postulated as the ligand entry channel in the opsin receptor and is occupied by lipid molecules in the recently solved crystal structure of the CXCR4 chemokine receptor, suggesting a general ligand entrance mechanism for nonpolar ligands to G protein-coupled receptors. The identification of a novel allosteric binding cavity in the TM domain of CXCR2, in addition to the previously identified intracellular binding site, shows the diversity in ligand recognition mechanisms by this receptor and offers new opportunities for the structure-based design of small allosteric modulators of CXCR2 in the future.

show abstract

“…Perturbations to the Hbonding networks involved in these equilibria may, in turn, propagate more global changes through influence on TM5 helical geometry and stability. Catecholamine agonist-induced signal propagation may arise from the dependence of helical conformations on these serine rotamer states (along with cysteines and threonines), especially within transmembrane helices (Deupi et al, 2010). In addition, the most conserved position in the TM5 of GPCRs, P5.50, is one turn below S5.46 and may further destabilize the TM5 helix, allowing the helix to swivel or kink to dynamically accommodate ligand associations (Del Carmine et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Transmembrane Segment Five Serines of the D4 Dopamine Receptor Uniquely Influence the Interactions of Dopamine, Norepinephrine, and Ro10-4548

Cummings

Ericksen²,

Goetz³

et al. 2010

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Conserved serines of transmembrane segment (TM) five (TM5) are critical for the interactions of endogenous catecholamines with ␣ 1 -and ␣ 2 -adrenergic, ␤ 2 -adrenergic, and D1, D2, and D3 dopamine receptors. The unique high-affinity interaction of the D4 dopamine receptor subtype with both norepinephrine and dopamine, and the fact that TM5 serine interactions have never been studied for this receptor subtype, led us to investigate the interactions of ligands with D4 receptor TM5 serines. Serine-to-alanine mutations at positions 5.42 and 5.46 drastically decreased affinities of dopamine and norepinephrine for the D4 receptor. The D4-S5.43A receptor mutant had substantially reduced affinity for norepinephrine, but a modest loss of affinity for dopamine. In functional assays of cAMP accumulation, norephinephrine was unable to activate any of the mutant receptors, even though the agonist quinpirole displayed wild-type functional properties for all of them. Dopamine was unable to activate the S5.46A mutant and had reduced potency for the S5.43A mutant and reduced potency and efficacy for the S5.42A mutant. In contrast, Ro10-4548 [RAC-2Ј-2-hydroxy-3-4-(4-hydroxy-2-methoxyphenyl)-1-piperazinyl-propoxy-acetanilide], a catechol-like antagonist of the wild-type receptor unexpectedly functions as an agonist of the S5.43A mutant. Other noncatechol ligands had similar properties for mutant and wild-type receptors. This is the first example of a dopamine receptor point mutation selectively changing the receptor's interaction with a specific antagonist to that of an agonist, and together with other data, provides evidence, supported by molecular modeling, that catecholamine-type agonism is induced by different ligand-specific configurations of intermolecular H-bonds with the TM5 conserved serines.The D4 dopamine receptor has had a checkered history of popularity. It was for a time believed to be the ideal target for an atypical antipsychotic drug (for review see Schetz and Sibley, 2007;Schetz, 2009). The D4 receptor has also been pursued as a drug target for treating attention-deficit hyperactivity disorder (ADHD) and erectile dysfunction, but these possibilities remain controversial. A D4 polymorphic variant (D4.7) was reported to be hyporesponsive to dopamine and associated with a higher risk for ADHD (LaHoste et al., 1996). However, the relevance of a low-magnitude hyporesponsiveness is unclear, and the association of the D4.7 polymorphic variant has not always been replicated by different laboratories (for a review see Schetz and Sibley, 2007) with some studies even suggest-

show abstract

Influence of the g− conformation of Ser and Thr on the structure of transmembrane helices

Cited by 27 publications

References 44 publications

Ligand chain length drives activation of lipid G protein-coupled receptors

Ligand chain length drives activation of lipid G protein-coupled receptors

Identification of a Novel Allosteric Binding Site in the CXCR2 Chemokine Receptor

Transmembrane Segment Five Serines of the D4 Dopamine Receptor Uniquely Influence the Interactions of Dopamine, Norepinephrine, and Ro10-4548

Contact Info

Product

Resources

About