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Table 2 Phenotypic concentration-responses for allosters in 10 sub-models from TCM

From: Allosteric transition: a comparison of two models

Type of TCM model # Enhancement w/ ceiling Allo-agonism w/ ceiling Strict allo-synergy Allo-modification w/ ceiling → ↓
(S)/4 1 no na no na no modifier - EC50
(S+MS)/4 2 yes yes no na no competitive
(S+M+MS)/4 3 yes yes yes no no na
(S+M)/4 4 no na inverse yes no yes
(MS)/4 5 (yes) yes no na (yes) na
(S)/3 6 no na no na no modifier - EC50
(S+MS)/3 7 yes no na no no
(MS)/3 8 (yes) no no na (yes) no
(S)/3* 9 no na no na no competitive**
(S+M)/3* 10 no na yes no no no
  1. For model types in the left column, terms S, M, and MS in parenthesis indicate active forms of the liganded receptor as either R*S, M*R or MR*S, and with the total number of receptor conformations after the slash. In models 6–8, complex MR is not formed. Model 7 is the classical uncompetitive reaction scheme. * In models 9–10, complex MRS is not formed. **Model 9 is classical type II reaction scheme for competitive inhibition with no ceiling, the same as assuming parameter c = 0. Arrows indicate direction of affinity change and direction of ceiling effects.
  2. na = not applicable, (yes) indicates that there is an effect in form of co-agonism, i.e., no response for ligand S alone.
  3. Simulations of concentration-response relations for tabulated sub-models 1–4, in column 2, are shown in Figure 4 panels A-I. S stands for orthoster and M for alloster. Ceiling effects for enhancement (= parameter c > 1) in sub-model 2 starts at A m· M > 1, panel D in Figure 4. Allo-competitive antagonism (= parameter c < 1) in sub-model 2 requires c·A m·M > 10 for a ceiling effect to appear. Thus, sub-model 2 simulates genuine competitive antagonism as long as the product c·A m·M is below 10, Figure 4 panel F. This dependence on product A m·M > 1 for ceiling effects of enhancement and on product c·A m·M >10 for ceiling effects in allo-competitive inhibition are also characteristics of both ATSM, Figure 5 panels A and C, and EXOM, Figure 5 panels D and F.
  4. Tabulated ternary-complex sub-model 1 and 6 with parameter c < 1 are characterized as (mixed) modifier mechanisms in enzymology. Their mixed allo-modification includes a possible simulation of classical non-competitive antagonism with a fixed EC50, when c = 1, Figure 4 panel B. Furthermore, both sub-models 1 and 6 have increasing affinity for increasing modifier concentration, indicated by EC50 ↓ in column 8. Sub-type model 4, excluding the ternary complex MRS as active, may show inverse agonism with decreasing ceiling values for the apparent affinity EC50 when parameter c > 1 and increasing ceiling levels for EC50 when parameter c < 1, Figure 4 panels J-L.
  5. Sub-models 5 and 8 demonstrate co-agonism, which means that both ligand S and ligand M have to be present for an activity to show up, simulations not shown.
  6. Sub-model 7 is identical to the classical un-competitive reaction scheme. Sub-models 9 and 10 are based on the classical type II competitive reaction scheme, excluding the double-liganded MRS conformation ([18] chapter 2), and therefore do not qualify as true TCMs.
  7. Two characteristics for ATSM and EXOM are not covered by any of the listed TCM reaction schemes in Table 2, viz. a strict allo-synergy, Figure 5 panels M and N, and ceiling effects for allo-agonism, compare Figure 4 panels G-I with Figure 5 panels G-H, J-K, M-N, Q-R, and T-U.