Tachykinin receptors structure

Almeida TA, Rojo J, Nieto PM et al (2004) Tachykinin and tachykinin receptors structure activity relationships. Curr MedChem 11 2045-2081... 

L-Diphenylalanine is a constrained amino acid which has been used for structure-activity studies on the tachykinin receptor.25.26 Despite its steric hindrance, this amino acid... 

As an example of a similar approach using in vivo SNAAR, Turcatti et aL" " incorporated a fluorescent amino acid, 3-N-(7-nitrobenz-2-oxa-l,3-diazol-4-yl)-2,3-diaminopropionic acid (NBD-Dpr), at specific sites in the tachykinin neurokinin-2 receptor, a member of the large family of seven a-helix G-protein coupled receptors (GPCRs). The expression system, Xenopus oocytes, allowed for functional assays of the receptor. Structural information was obtained by measuring the intermolecular distance between the fluorescent amino acids placed at different sites and a fluorescently labeled heptapeptide antagonist using fluorescence resonance energy transfer (FRET). 

Satake H, Kawada T (2006) Overview of the primary structure, tissue distribution, and function of tachykinins and their receptors. Curr Drug Targets 7 963-974... 

Tachykinins are among the most abundant neuropeptides in the central nervous system. Limbic structures, which are important in the control of emotional behaviors, in particular contain tachykinins and neurokinin receptor sites in high density (Honkaniemi et al. 1992 Hurd et al. 1999 Ribeiro-da-... 

Donnelly, D., Maudsley, S., Gent, J. P., Moser, R. N., Hurrell, C. R., Findlay, J. B. C. Conserved polar residues in the transmembrane domain of the human tachykinin NK2 receptor Functional roles and structural implications. Biochem. J., 1999, 339, 55-61. 

All structures were selected from the Ensemble database. In addition to approved therapeutic agents these particularly include a set of lead compounds entered in advanced clinical/preclinical trials (a total of 16,540 compounds). Structures were extracted according to the assigned activity class, where the class indicates a common target-specific group such as GPCRs, kinases and proteases, nuclear receptors, and ion channels as well as more than 150 subclasses (for example, serotonin, tachykinin and dopamine receptors, tyrosine, Abl, Aurora and serine/threonine kinases, cysteine and serine proteases, etc.). Prior to the statistical experiments, the molecular structures should be filtered and normalized in order to fulfill certain criteria (see Subheading 3.5 and 4). 

Because of specific cluster structure determined by the internal activation (neuron) function originally realized in the Kohonen-based SOMs it is very difficult to obtain a fully scalable and, at the same time, adequate map with the preservation of all the distances observed among all input samples. Fortunately, using the constructed map it is quite possible to set the zoom into the GPCR area. Thus, compounds acting specifically on different GPCR subclasses including a/ p-adrenoceptors, dopamine D1-D4 receptors, tachykinin NK1/NK2, serotonin and chemokine receptors can also be successfully separated within the same map (Fig. 3a-i). 

A. Chollet, Probing the structure and function of the tachykinin neurokinin-2 receptor through biosynthetic incorporation of fluorescent amino acids at specific sites,/. Biol. Chem. 1996, 271, 19991-19998. 

Several multi-ligand/multi-receptor systems are known in which multiple structurally related peptide hgands bind to various GPCRs that belong to a common receptor family. The neuropeptide Y family, the tachykinin system and the melanocortin system, just to mention a few, are known to exhibit important functions in the organism and therefore have been intensively investigated for years by SAR studies based on synthetically derived analogs. 

Xurcatti, G., Nemeth, K., Edgerton, M.D., Meseth, U., Talabot, F., Peitsch, M., Knowles, J., Vogel, H., and ChoUet, A., Probing the structure and function of the tachykinin neurokinin-2 receptor through biosynthetic incorporation of fluorescent amino acids at specific sites, /. Biol. Chem., 271, 33,19991,1996. 

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