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Identification Of Receptors In Vitro
Published in William C. Eckelman, Lelio G. Colombetti, Receptor-Binding Radiotracers, 2019
If log{(Bo − B)/B} is plotted against log[I], a straight line results with slope of 1.0. A straight line on a Hill plot is therefore consistent with simple competitive inhibition. The presence of negative cooperativity (for the inhibitor) or of two sites with different affinity (for the inhibitor) results in a Hill plot with slope less than 1.0. Positive cooperativity or irreversible binding of the inhibitor gives a Hill plot with a slope greater than 1.0. The slope of a Hill plot is called the Hill coefficient. For several neurotransmitter receptors, agonists show Hill coefficients between 0.5 and 1.0, when competed against labeled antagonists. This appears to be due to the existence of two classes of site for agonists.
Red Cells with High Oxygen Affinity Hemoglobins
Published in Ronald L. Nagel, Genetically Abnormal Red Cells, 2019
where n is the Hill coefficient, or an empiric number that is a measure of the sigmoidicity of the curve and is related to the extent of cooperativity. The Hill coefficient is 2.8 for hemoglobin and 1, of course, for myoglobin.
Mechanisms of Ca2+ Transport in Myometrium
Published in Robert E. Garfield, Thomas N. Tabb, Control of Uterine Contractility, 2019
Sergey A. Kosterin, Th. V. Burdyga, V. P. Fomin, Ashok Kumar Grover
PM and ER of the uterine SMC can absorb Ca2+ at high- and low-affinity binding sites.46,56,60,90 K0.5 for Ca2+ of high-affinity binding sties of the PM at pH > 7 is 0.3 μ M and the value of the Hill coefficient is > 2. Acidification (pH < 6) of the incubating medium significantly decreases Ca2+ affinity of the PM (Figure 5).46 High-affinity binding of Ca2+ is lowered by Mg2+, Na+, and K+, with Ki of 1.8, 19, and 233 m M, respectively.40 PM of the bovine uterine SMC shows low-affinity binding sites with K0.5 for Ca2+ of 80–90 μ M.56,60 Lowering pH from 8.0 to 6.0 also decreases Ca2+-binding capacity of the low-affinity binding sites.24
A molecular perspective on identifying TRPV1 thermosensitive regions and disentangling polymodal activation
Published in Temperature, 2023
Dustin D. Luu, Aerial M. Owens, Mubark D. Mebrat, Wade D. Van Horn
In the concatemer and other studies, a Hill model of cooperativity can be used to assess the allosteric implications between multiple ligand-binding sites [189]. A Hill coefficient (Kd) for additional oxygen-binding molecules [190]. Highly positive cooperative events, like found in hemoglobin, will generally have minimal intermediate bound states with an “all or nothing” binding process. In the context of hemoglobin, which is exceptionally cooperative, it is typically found in either an unbound or fully bound state [191]. Conversely, negative cooperativity functions to decrease the affinity of ligand binding as more ligands bind the substrate. The outcomes of negative cooperativity are more populated and longer-lasting intermediate bound states [191]. A noncooperative process effectively has independent binding sites [191]. Analysis of the rTRPV1–CAP concatemer study identifies a Hill coefficient near unity, indicating that CAP activation is noncooperative. This appears to agree with the conclusion that CAP binding to a single subunit can fully open rTRPV1 [180]. In contrast, rTRPV1 concatemer proton activation exhibits positive cooperativity (4,180]. The reported differences in cooperativity between CAP and protons shines a light on mechanistically distinct TRPV1 activation modes and provide a vignette into the complexity of deciphering the polymodal crosstalk between activation modes.
Spectroscopic observations of β-eudesmol binding to human cytochrome P450 isoforms 3A4 and 1A2, but not to isoforms 2C9, 2C19, and 2D6
Published in Xenobiotica, 2022
Dawid Krenc, Kesara Na-Bangchang
Absorption values were normalised to 1.0 cm light path length (A1cm) by multiplying with the factor [340 μL/(sample volume) μL]. Solvent-corrected ligand-binding difference spectra were calculated with Microsoft Excel. Difference peak (λmax) and trough (λmin) wavelengths were estimated, and the corresponding peak-to-trough absorption difference (ΔA1cm) was calculated (Supplementary Figures 6 and 7). Spectroscopic P450-ligand binding constants (Ks) were estimated by simple non-linear regression with GraphPad Prism, versions 9.0–9.3 (GraphPad Software, San Diego, CA). The GraphPad regression option selected was: ‘Receptor binding; Specific binding with Hill slope’. Specific binding, rather than total binding, was selected because this method yielded Ks estimates for all experiments, in particular for the low CYP1A2-affinity ligand CAF. The corresponding formula was max (‘B for binding’) is the estimated maximal peak-to-trough absorption difference, c is the ligand concentration, and n is the Hill coefficient. Both ΔA and Bmax refer to a light path length of 1.0 cm. Statistical differences between two groups were determined with GraphPad Prism, using Welch’s t test (unpaired, normal, SD not equal) at a statistical significance level of α =0.05.
Main contribution of UGT1A1 and CYP2C9 in the metabolism of UR-1102, a novel agent for the treatment of gout
Published in Xenobiotica, 2021
Mizuki Yamane, Fumihiko Igarashi, Tsuyoshi Yamauchi, Toshito Nakagawa
To estimate fm_UGT1A1, the IC50 values and the Hill coefficients obtained from rhUGT1A1 and rhUGT1A3 were used to fit the inhibition curve in HLM to the observed values with the following equation: I represents the percentage of UR-1102 glucuronide formation inhibited in HLM, and C represents the concentration of atazanavir. The values for IC50a and Hilla were obtained from rhUGT1A1, and the values for IC50b, and Hillb were obtained from rhUGT1A3 using Equation (4). The fraction metabolised by UGT1A3 was calculated by subtracting fm_UGT1A1 from 1. IrhUGT represents the percentage of UR-1102 glucuronide formation inhibited in rhUGT1A1 or rhUGT1A3, and S represents the concentration of atazanavir. The optimal IC50 and Hill coefficient were obtained via the Michaelis–Menten or Hill equations, which give lower Akaike's information criterion. The Hill coefficient was 1 when the Michaelis–Menten equation was selected. These data analyses were carried out using WinNonlin software.