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Intrinsic activity at the molecular level: E. J. Ariëns' concept visualized
D J Abraham1, J Kister, G S Joshi
1Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond 23298, USA.
Journal of Molecular Biology
|May 12, 1995
Summary
Drug molecules interact with receptors based on affinity and intrinsic activity. This study reveals that hemoglobin allosteric effectors with similar binding affinities can exhibit different effectiveness, impacting oxygen affinity.
Area of Science:
- Pharmacology
- Biochemistry
- Structural Biology
Background:
- Drug interactions with receptors are historically analyzed using affinity and intrinsic activity.
- Intrinsic activity, a drug's effectiveness upon binding, was previously attributed to physicochemical processes.
Purpose of the Study:
- To investigate the molecular basis of intrinsic activity in allosteric effectors of hemoglobin.
- To determine if effectors with similar binding affinities exhibit varying degrees of effectiveness.
Main Methods:
- Detailed oxygen and solution binding experiments.
- X-ray crystallographic studies on hemoglobin allosteric effectors.
- Analysis of effector binding constants and their effect on allosteric equilibrium.
Main Results:
- Allosteric effectors bound to the same site on hemoglobin with similar binding constants.
- Effectors induced different shifts in the allosteric equilibrium and oxygen affinity of the T-state.
- Intrinsic activity varied among effectors despite similar binding affinities.
Conclusions:
- The source of varying intrinsic activity lies in the effector's interaction with specific residues, such as Lys99 alpha, at the binding site.
- A general molecular mechanism for allosteric effector modulation of hemoglobin function is proposed.
- This mechanism may be applicable to other allosteric enzyme systems.