Active State-like Conformational Elements in the β₂-AR and a Photoactivated Intermediate of Rhodopsin Identified by Dynamic Properties of GPCRs

Abstract

G-Protein-coupled receptors (GPCRs) adopt various functionally relevant conformational states in cell signaling processes. Recently determined crystal structures of rhodopsin and the β2-adrenergic receptor (β2-AR) offer insight into previously uncharacterized active conformations, but the molecular states of these GPCRs are likely to contain both inactive and active-like conformational elements. We have identified conformational rearrangements in the dynamics of the TM7−HX8 segment that relate to the properties of the conserved NPxxY(x)5,6F motif and show that they can be used to identify active state-like conformational elements in the corresponding regions of the new structures of rhodopsin and the β2-AR.

Dopamine D1receptor and serotonin 5-HT1Areceptor agonist effects of the natural product (–)-stepholidine: molecular modelling and dynamics simulations

“…Therefore, specific 'state' to each GPCR conformations was associated with the 'state' of the FM [34].…”

Differential determinants for coupling of distinct G proteins with the class B secretin receptor

“…There is evidence that these motifs form ionic interactions or contribute to hydrogen bonding networks that help maintain the inactive state of receptors (16,66,75), and thus may only affect G protein coupling indirectly. In support of this assertion the structural data do not show any direct interactions of the G proteins with these motifs (53)(54)(55)(56).…”

“…Secretin receptor mutants were designed and prepared based on a careful review of studies that have examined sites critical to G protein coupling with other GPCRs (16,33,34,53,55,56,66,67,71,74,75), including the analysis of previous studies performed with other class B GPCRs (1, 4 -8, 12, 21, 22, 25-28, 38, 44, 45, 57, 62-64). Shown in Fig.…”

Towards a quantitative representation of the cell signaling mechanisms of hallucinogens: Measurement and mathematical modeling of 5-HT1A and 5-HT2A receptor-mediated ERK1/2 activation

“…These advances have improved our understanding of GPCR activation as an allosteric mechanism, triggered by ligand binding, that results in conformational changes transduced by the transmembrane domain (Han, Wang et al 2008) (Urban, Clarke et al 2007) (Weinstein 2006; Deupi and Kobilka 2007) (Kobilka and Deupi 2007). The advances have also allowed us to characterize the steps of intra-receptor activation mechanism by combing computational modeling and experimentation (Guo, Shi et al 2005).…”

“…The advances have also allowed us to characterize the steps of intra-receptor activation mechanism by combing computational modeling and experimentation (Guo, Shi et al 2005). Experimental evidence points to multiple conformations related to the activation of the receptor (Niv, Skrabanek et al 2006), (Filizola, Wang et al 2006; Han, Wang et al 2008). Different ligands binding to the same receptor may induce different conformational states, which in turn can result in coupling to different signaling pathways (specifically for the hallucinogens, see Gonzales-Maeso, Weisstaub et al 2007), and functional hetero-oligomarization (Gonzalez-Maeso, Ang et al 2008).…”