Steroid-protein interactions. 43. Influence of steroid structure and temperature on the binding of steroids to guinea pig corticosteroid-binding globulin

Abstract

To better understand the nature of the interactions between steroids and proteins, we have analyzed the thermodynamic and structural requirements of steroid binding by the corticosteroid-binding globulin purified from pregnant guinea pig serum. The affinity constant of the proteinsortisol complex is inversely related to temperature. At 4 OC the association of cortisol is enthalpy and entropy driven, whereas at 37 OC enthalpy is the driving force, Mo being negative. By comparison of the K, values determined by equilibrium dialysis for individual steroids that differ in only one structural change, the effect of this change on the binding affinity can be assessed. The steroid-binding site appears to be best adapted to bind cortisol; alteration of this structure invariably decreases the affinity. The free energy contributions by individual substituents are approximately additive in determining the total free energy of binding. For example, the low affinity of progesterone relative to cortisol for guinea pig corticosteroid-binding globulin results from the absence of the three T h e corticosteroid-binding globulin (CBG)' of the guinea pig exists at a relatively high concentration during late pregnancy and can be isolated from serum in pure form with a high yield (Mickelson & Westphal, 1979a). Guinea pig CBG has an affinity constant for cortisol that is -20 times larger than that for progesterone. Human CBG, in contrast, binds both cortisol and progesterone with similar affinity (Stroupe et al., 1978). In the present study, the affinity constants of guinea pig CBG complexes with a number of steroids have been determined in order to define the conditions producing strong or weak

Conformation of progesterone side chain: conflict between x-ray data and force-field calculations

“…Selected geometric parameters of the 16/8-methyl-substituted members of subgroup F are compared with the average values for these parameters for subgroup Al in Table II. In molecules having conformation FI, the carbonyl is 0.1 Á closer to C(16/3) than it is to C (18), probably due to the orientation of the hydrogen atoms on these carbons. The average C(13)-C( 17)-C(20) angle is 3°smaller than the value observed in subgroup Al and the average C(16)-C( 17)-C(20) angle is 4°l arger.…”

Development of Glucocorticoid-Responsiveness in Mouse Intestine

“…As the latter displays marked increases during the first 3 postnatal weeks (23,24), a given dose of natural glucocorticoid at early ages yields very much lower circulating concentrations than does the same dose at later ages (25). This problem can be obviated by the use of a synthetic glucocorticoid such as dexamethasone (DEX), which does not bind to corticosteroidbinding globulin (26). Thus, a given dose of DEX yields the same circulating concentration at various developmental stages (25).…”

3-D QSAR analysis of steroid/protein interactions: The use of difference maps

“…The example used is related to the affinities of human [4] and guinea-pig [5] CBG complexes with steroids.…”