Receptor contact site

The most well-characterized receptor contact site in G proteins is the extreme C-terminus of Ga (Fig. 4). Structural information for this region is lacking as the C-terminus is either absent or disordered in most... 

Fig. 4. Receptor contact sites on the G protein. Ribbon diagram of the heterotri-meric G protein (1GOT) with the C-terminal tail of Gat attached (1AQG), which has been rotated toward the viewer from the putative receptor-binding orientation to visualize the receptor contact sites (magenta).

Fig. 6. Structural elements connecting receptor contact sites to the nucleotidebinding pocket. The a5 helix and / 6 strand connect the C-terminus and a4// 6 loop to the nucleotide-binding pocket at the / 6/a5 loop (pink). The a3// 5 loop is connected to Switch III by the a3 helix (lime). Perturbations in Switch III may be communicated across the interdomain interface through its interactions with the aD/aE loop (lime). The aN helix is connected to the P-loop and Switches I and II through its interactions with ft strands 1-3 (teal). Additionally, these / strands also interact with the a5 helix (pink) and may participate in front-to-back communication between these elements.

Sullivan, K. A., Miller, R. T., Masters, S. B., Beiderman, B., Heideman, W., and Bourne, H. R. (1987). Identification of receptor contact site involved in receptor-G protein coupling. Nature 330, 758-760. 

While it has been known for many years that the N-terminal presequence is sufficient to promote mitochondrial targeting and assembly, the subsequent interaction of the precursor molecule with the outer mitochondrial membrane and the uptake of the protein is still an area of active research. There seems little doubt, however, that there are proteins on the outer mitochondrial membrane which are required for the import process. The function of these proteins is uncertain, but they may act as receptors with the subsequent transfer through the membrane at proteinous pores located at contact sites between the inner and outer membranes. Several proteins have been identified which seem to play an important role as either receptor proteins or part of the import channel (Pfanner et al., 1991). Again, not all proteins seem to depend on this mechanism. Cytochrome c, which is loosely associated with the outer aspect of the inner mitochondrial membrane, can cross... 

Alternatively, binding affinity between the mimetic ligand and receptor might be achieved by a different mechanism than that of the natural ligand. The mimetic ligand might contact a different area of the receptor binding site, or provide a different set of intermolecular interactions. As shown in... 

The canyons are depressions approximately 15 to 20 A deep that encircle each icosahedral five-fold axis (Figure 1). When first seen in HRV 14, these canyons were postulated to be the site at which a cellular receptor would bind. Subsequent electron-microscopic data revealed that ICAM-1 does indeed bind in the canyon as predicted, although in a somewhat different orientation than early models [22,23]. These canyons allow the receptor binding sites to escape immunological surveillance because the canyons are too narrow to allow an immunoglobulin to contact the canyon floor. Directly underneath the floor of the canyon lies a second important structure, the VP1 hydrophobic pocket. 

Despite the extensive data describing the receptor-binding surface on G proteins, much less is known about the specific point-to-point interactions between these proteins. Generally, the membrane-proximal sections of IC 2, 3, and 4 form the primary interaction surface on the receptor. Additional contact sites in the transmembrane helices may also be formed as the Gy C-terminus enters deeply into the pocket formed in the cytoplasmic face of the receptor on activation (Janz and Farrens, 2004). Peptides corresponding to IC 2, 3, and 4 block the stabilization of Meta II by Gat (Konig et at., 1989 Marin et at., 2000). A reverse substitution approach, where each intracellular loop was replaced with polyalanine sequences and then individual alanine residues were mutated back to the native amino acid, demonstrated that residues adjacent to the transmembrane helices in these loops were the most important for G protein activation (Natochin et at., 2003). 

Liu, J., Conklin, B. R., Blin, N., Yun, J., and Wess, J. (1995). Identification of a receptor/G-protein contact site critical for signaling specificity and G-protein activation. Proc. Natl. Acad. Sci. USA 92, 11642-11646. 

Perret, P., Laube, B., Schemm, R., Betz, H., Goeldner, M. and Foucaud, B. (2002). Affinity labeling of cysteine-mutants evidences contact residues in modeled receptor binding sites. J. 

Information transfer between two neurons or between neurons and effector cells involves the release of chemical substances, which then act on the target cell by binding to appropriate receptors embedded in the plasma membrane. This process, as originally described by Otto Loewi (Loewi 1921), is termed chemical neurotransmission and occurs at contact sites known as synapses. Neurotransmitters exert their effects via members of two major families of receptors ionotropic and metabotropic neurotransmitter receptors. Activation of ionotropic receptors leads to an increase in the ion conductance of the membrane within a time scale of milliseconds or even less, whereas activation of metabotropic receptors results in slow effects (within seconds or even minutes) which involve more or less complex signaling cascades. Accordingly, information transfer via ionotropic receptors is called fast synaptic transmission, whereas the slow counterpart is called neuromodulation (Kaczmarek and Levitan 1987). 

Behrendt N, Ronne E, Dano K. Domain interplay in the urokinase receptor. Requirement for the third domain in high affinity ligand binding and demonstration of ligand contact sites in distinct receptor domains. J Biol Chem 1996 271(37) 22885-22894. 

Krieger-Brauer, H. 1., Medda, P. K., Hebling, U., Kather, H. An antibody directed against residues 100-119 within the a-helical domain of Gas defines a novel contact site for (3-adrenergic receptors. J. Biol. Chem., 1999, 274, 28308-28313. 

Exposure assessment includes both qualitative and quantitative evaluations of the potential for exposure to site-related chemicals to occur. Assessments commonly address both current and likely future uses of the property (e.g., residential, commercial, industrial, and agricultural). Typically, a conceptual model is developed that summarizes how site-related chemicals may contact receptors (e.g., humans, wildlife, and ecological). The model includes identification of chemical sources, impacted media, potential movement through the environment, identification of the appropriate exposure scenarios, and identification of the points at which contact between receptors and site-related chemicals are likely to occur. Chemical concentrations in environmental media may be estimated based on site data and using statistical analyses and/or fate and transport modeling. An estimate of the dose (intake) attributable to contact with environmental media through significant and completed pathways is made for chemicals of concern at... 

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