Loops extracellular

Fig. 5. Schematic diagram of the presumed arrangement of the amino acid sequence for the 5-opioid receptor, showing seven putative transmembrane segments three intracellular loops, A three extracellular loops, B the extracellular N-terrninus and the intracellular C-terrninus, where (0) represents amino acid residues common to ] -, 5-, and K-receptors ( ), amino acid residues common to all three opioid receptors and other neuropeptide receptors and (O), other amino acids. Branches on the N-terruinal region indicate possible glycosylation sites, whereas P symbols in the C-terminal region indicate...

Kleinau G, Claus M, Jaeschke H et al (2007) Contacts between extracellular loop two and transmembrane helix six determine basal and hormone induced activity of the thyroid stimulating hormone receptor. J Biol Chem 282(1 ) 518-25... 

The structure of all TK receptors is similar in terms of expression oiTACR genes, since all these genes contain five exons intercalated by four introns [1, 5]. Exon I encodes for the N-terminal extracellular tail, the first intracellular (IC1) and extracellular (EC1) loops and the first, second, and third transmembrane domains (TM1, TM2, and TM3). Exon II encodes for the second intracellular (IC2) and extracellular (EC2) loops and the fourth transmembrane domain (TM4). Exon III encodes for the fifth transmembrane domain (TM5) and the third intracellular loop (IC3). Exon IV encodes for the sixth and seventh transmembrane domains (TM6 and TM7) and the third extracellular loop. Exon V encodes for the C-terminal intracellular tail only. A schematic drawing of the amino acid sequences and TK receptor organization is shown in Fig. 1. 

Figure 3.4 Transmembrane topology of a 7-TM domain G-protein receptor such as the P-adrenoceptor. Agonist binding is predicted to be within the transmembrane domains. The extracellular structure is stabilised by the disulphide bond joining the first and second extracellular loop. The third intracellular loop is the main site of G-protein interaction while the third intracellular loop and carboxy tail are targets for phosphorylation by kinases responsible for initiating receptor desensitisation...

Fig. 1. Diagrammatic representation of CCR7 showing the arrangement of the transmembrane domains, the intra- and extracellular loops, and the amino-terminus and carboxy-terminus.

Data from studies with other GPCRs have highlighted the importance of extracellular cysteines in ligand binding and the maintenance of the conformational integrity of the receptors. There are typically four conserved cysteine residues found on extracellular domains of chemokine receptors (see Figure 1 and Tables 2 and 3) one on the amino-terminus and one on each of the three extracellular loops. It is clear that the cysteines on extracellular loops 1 and 2 form a disulfide bond that is essential for the proper trafficking of the receptors... 

Zoffmann S, Chollet A, Galzi JL. Identification of the extracellular loop 2 as the point of interaction between the N terminus of the chemokine MIP-lalpha and its CCR1 receptor. Mol Pharmacol 2002 62(3) 729-736. 

Samson M, LaRosa G, Libert F, et al. The second extracellular loop of CCR5 is the major determinant of ligand specificity. J Biol Chem 1997 272(40) 24934-24941. 

Understanding the nature of the domains or elements on the chemokine receptor coreceptors is also of significant importance, especially with regard to the development of coreceptor-blocking therapeutics. HIV-1 gpl20 interacts with multiple extracellular domains of the chemokine receptors to mediate binding, and the N-terminus and extracellular loop (ECL) number 2 of CCR5... 

Most of the G-protein-coupled receptors are homologous with rhodopsin however, other quantitatively minor families as well as some individual receptors do not share any of the structural features common to the rhodopsin family (Figure 2.3). The most dominant of these are the glucagon/VIP/caldtonin receptor family, or family B (which has approximately 65 members), and the metabotropic glutamate receptor family, or family C (which has approximately 15 members), as well as the frizzled/smoothened family of receptors. Thus, the only structural feature that all G-protein-coupled receptors have in common is the seven-transmembrane helical bundle. Nevertheless, most non-rhodopsin-like receptors do have certain minor structural features in common with the rhodopsin-like receptors — for example, a disulfide bridge between the top of TM-III and the middle of extracellular loop-3, and a cluster of basic residues located just below TM-VI. 

FIGURE 2.3 The three main families of mammalian G-protein-coupled 7TM receptors in mammals. No obvious sequence identity is found between the rhodopsin-like family A, the glucagon/VIP/calcitonin family B, and the metabotropic glutamate/chemosensor family C of G-protein-coupled 7TM receptors, with the exception of the disulfide bridge between the top of TM-III and the middle of extracellular loop-2 (see Figure 2.2). Similarly, no apparent sequence identity exists among members of these three families and, for example the 7TM bitter taste receptors, the V1R pheromone receptors, and the 7TM frizzled proteins, which all are either known or believed to be G-protein-coupled receptors. Bacteriorhodopsins, which are not G-protein-coupled proteins but proton pumps, are totally different in respect to amino-acid sequence but have a seven-helical bundle arranged rather similarly to that for the G-protein-coupled receptors. 

One of the most highly conserved features among 7TM receptors is the disulfide bridge between the Cys at the top of TM-III and a Cys situated somewhere in the middle of the second extracellular loop. This loop is thereby transformed into two loops connecting the top of TM-III with the top... 

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